Andreoli and Carpenter's Cecil Essentials of Medicine, 8th Edition (Cecil Medicine)

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Author: Thomas E. Andreoli MD MACP FRCP(Edin) | Ivor Benjamin MD FACC FAHA | Robert C. Griggs MD FACP FAAN | Edward J Wing MD | J. Gregory Fitz MD

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ANDREOLI and CARPENTER’S Cecil

Essentials of

MEDICINE 8th EDITION

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ANDREOLI and CARPENTER’S Cecil

Essentials of

MEDICINE 8th EDITION Editor-in-Chief THOMAS E. ANDREOLI, MD, MACP, FRCP (Edin.), FRCP (London), ScD (hon.), Docteur (hon.), MD (hon.)†

Distinguished Professor Nolan Chair Emeritus Department of Internal Medicine Department of Physiology and Biophysics University of Arkansas College of Medicine Little Rock, Arkansas (†Deceased)

Editors Ivor J. Benjamin, MD, FACC, FAHA Professor of Medicine Adjunct Professor of Biochemistry Christi T. Smith Endowed Chair for Cardiovascular Research Director, Center for Cardiovascular Translational Biomedicine University of Utah School of Medicine Salt Lake City, Utah

Robert C. Griggs, MD, FACP, FAAN Professor of Neurology, Medicine, Pediatrics, and Pathology and Laboratory Medicine University of Rochester School of Medicine and Dentistry Rochester, New York

Edward J. Wing, MD, FACP, FIDSA Dean of Medicine and Biological Sciences The Warren Alpert Medical School of Brown University Providence, Rhode Island

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 ANDREOLI AND CARPENTER’S CECIL ESSENTIALS OF MEDICINE

ISBN: 978-1-4160-6109-0

International Edition

ISBN: 978-0-8089-2428-9

Copyright © 2010 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2007, 2004, 2001, 1997, 1993, 1990, 1986 by Saunders, an imprint of Elsevier Inc. Library of Congress Cataloging-in-Publication Data Andreoli and Carpenter’s Cecil essentials of medicine / editor-in-chief, Thomas E. Andreoli; editors, Ivor J. Benjamin, Robert C. Griggs, Edward J. Wing.—8th ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4160-6109-0 1. Internal medicine—Textbooks. I. Andreoli, Thomas E., 1935-2009 II. Cecil, Russell L. (Russell La Fayette), 1881-1965. III. Title: Cecil essentials of medicine. IV. Title: Essentials of medicine. [DNLM: 1. Internal Medicine. WB 115 A559 2010] RC46.C42 2010 616—dc22 2009027158 Cover: Hemoglobin subunit: Phantatomix / Photo Researchers, Inc.; False-color (computer graphics) photograph of a resin cast of the human bronchial tree, the network of airways serving both lungs: Alfred Pasieka / Photo Researchers, Inc.; DNA: Dr. A. Lesk, MRC-LMB / Photo Researchers, Inc.; Osteoarthritis of foot, X-ray: DR P. MARAZZI / Photo Researchers, Inc. Acquisitions Editor: James Merritt Managing Editor: Rebecca Gruliow Publishing Services Manager: Linda Van Pelt Project Manager: Sharon Lee Design Direction: Steven Stave Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1

Working together to grow libraries in developing countries www.elsevier.com | www.bookaid.org | www.sabre.org

Dedication Thomas E. Andreoli When Dr. Thomas Andreoli died of a cerebral hemorrhage on April 14, 2009, he had nearly completed the editorial oversight of this, the eighth edition of the textbook he co-founded in 1986. In many ways this textbook epitomizes his career as an educator, clinical scientist, and international leader of the medical profession. As an outstanding, life-long investigator in his chosen field of nephrology, Dr. Andreoli served as president of both national and international medical societies and was recognized by honorary doctoral degrees from both European and American universities. As a dedicated bedside clinician and teacher, Dr. Andreoli served as an outstanding chair of medicine, and endowed chairs in his name were established at both the University of Alabama School of Medicine and the University of Arkansas College of Medicine. His superlative teaching was recognized by his receiving, inter alia, the Louis Pasteur Award from the University Louis Pasteur, Mastership of the American College of Physicians, and the Robert H. Williams Distinguished Chair of Medicine Award from the Association of Professors of Medicine. Perhaps Dr. Andreoli’s most distinguished contribution was his lifelong Oslerian devotion to translating medical science from bench to bedside. Despite his major national and international commitments, he continued throughout his career to hold morning resident teaching rounds five times weekly, maintaining a broad knowledge of all aspects of internal medicine and genuinely and gently transmitting that knowledge to two generations of medical students. He was uniquely qualified for, and committed to, imparting his wisdom and skill as a physician, which provided the basis for his serving as a founding editor of Essentials of Medicine, and editor-in-chief of its last three editions. We feel immensely privileged to have been his co-editors and friends, and we dedicate this text to Dr. Thomas Andreoli. Charles C. J. Carpenter, MD, MACP Professor of Medicine Brown Medical School Director, Brown University AIDS Center Providence, Rhode Island

Clementine M. Whitman No tribute to Dr. Andreoli’s accomplishments would be complete without acknowledging the contributions of Clementine Whitman, his personal assistant of 40 years, who moved with him from Alabama to Texas and to Arkansas. Clementine was the hub of Dr. Andreoli’s professional and personal life, meticulously handling every detail. Dr. Andreoli, a man as demanding of others as of himself, was indeed blessed and fortunate to have such a talented, dedicated, loyal, and hard-working person by his side. Sudhir V. Shah, MD, FACP Professor of Medicine Director, Division of Nephrology University of Arkansas College of Medicine Little Rock, Arkansas Chief, Renal Section, Medicine Service John L. McClellan Memorial Veterans Hospital Little Rock, Arkansas


Andreoli and Carpenter’s Cecil Essentials of Medicine International Advisory Board NAME

DISCIPLINE

COUNTRY

Professor J. S. Bajaj Chief Consultant and Director Department of Diabetes, Endocrine and Metabolic Medicine Batra Hospital and Medical Research Centre New Delhi, India [email protected]

Endocrinology

India

Professor Massimo G. Colombo, MD Professor and Chairman Department of Gastroenterology and Endocrinology IRCCS Maggiore Hospital University of Milan Milan, Italy [email protected]

Hepatology/Gastroenterology

Italy

Professor Bertrand Fontaine, MD Professor of Neurology Faculté de Médecine Fédération des Maladies du Système Nerveux Groupe Hospitalier Pitié-Salpêtrière Paris, France [email protected]

Neurology

France

Professor Arnoldo Guzmán-Sanchez Professor and Chair Department of Obstetrics and Gynecology Hospital Civil de Guadalajara Guadalajara, Jalisco, Mexico [email protected]

Women’s Health

Mexico

Professor Kiyoshi Kurokawa, MD President, Science Council of Japan Professor Emeritus, University of Tokyo Roppongi, Minato-ku Tokyo, Japan [email protected]

Nephrology

Japan

Professor Umesh G. Lalloo, MD, FCCP Head, Department of Pulmonology and HIV Nelson R. Mandela School of Medicine University of Kwa-Zulu Natal Durban, South Africa [email protected]

General Internal Medicine/HIV

South Africa

Professor Pal Magyar Head, Department of Pulmonary Medicine Semmelweis University Budapest, Hungary [email protected]

Pulmonary Medicine

Hungary

Professor John Newsom-Davis, MD Emeritus Professor of Clinical Neurology Radcliffe Infirmary Woodstock Road Oxford, United Kingdom [email protected]

Neurology

United Kingdom

NAME

DISCIPLINE

COUNTRY

Professor J. N. Pande Professor of Medicine Department of Infectious Diseases Sita Ram Bhartia Institute of Science and Research All India Institute of Medical Sciences New Delhi, India [email protected]

Infectious Diseases

India

Dr. Mario Paredes-Espinoza Professor and Chair Department of Internal Medicine Hospital Civil Fray Antonio Alcalde Guadalajara, Jalisco, Mexico [email protected]

Men’s Health/General Internal Medicine

Mexico

Professor Nestor Schor, MD, PhD Head Professor of Medicine Nephrology Division UNIFESP-Escola Paulista de Medicina São Paulo, Brazil [email protected]

Nephrology

Brazil

Lead Authors and Contributors Section I Introduction to Molecular Medicine Lead Author Ivor J. Benjamin, MD, FACC, FAHA Professor of Medicine Adjunct Professor of Biochemistry Christi T. Smith Endowed Chair in Cardiovascular Research Director, Center for Cardiovascular Translational Biomedicine University of Utah School of Medicine Salt Lake City, Utah [email protected]

Section II Evidence-Based Medicine Lead Authors Sara G. Tariq, MD Associate Professor Department of Internal Medicine University of Arkansas College of Medicine Little Rock, Arkansas [email protected] Susan S. Beland, MD Associate Professor Department of Internal Medicine University of Arkansas College of Medicine Little Rock, Arkansas [email protected]

Section III Cardiovascular Disease Lead Author Ivor J. Benjamin, MD, FACC, FAHA Professor of Medicine Adjunct Professor of Biochemistry Christi T. Smith Endowed Chair in Cardiovascular Research Director, Center for Cardiovascular Translational Biomedicine University of Utah School of Medicine Salt Lake City, Utah [email protected] Contributors David Bull, MD Professor of Surgery Director, Thoracic Surgery Residency Program University of Utah School of Medicine Chief of Cardiothoracic Surgery Salt Lake City VA Medical Center Salt Lake City, Utah [email protected]

Mohamed H. Hamdan, MD Professor and Associate Division Chief Division of Cardiology University of Utah School of Medicine Section Chief, Arrhythmia University of Utah Healthcare Salt Lake City, Utah [email protected] Dean Y. Li, MD, PhD Associate Professor Departments of Medicine and Oncological Science Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City, Utah [email protected] Sheldon E. Litwin, MD Amundsen Professor of Internal Medicine/Cardiology Director of Cardiovascular Imaging University of Utah Hospital University of Utah School of Medicine Salt Lake City, Utah [email protected] Andrew D. Michaels, MD Associate Professor of Internal Medicine Director, Cardiac Catheterization Laboratory and Interventional Cardiology University of Utah School of Medicine Salt Lake City, Utah [email protected] Jack H. Morshedzadeh, MD Instructor Division of Cardiology University of Utah School of Medicine Salt Lake City, Utah [email protected] Josef Stehlik, MD Assistant Professor of Internal Medicine Division of Cardiology University of Utah School of Medicine Salt Lake City, Utah [email protected] Kevin J. Whitehead, MD Associate Professor of Cardiology University of Utah School of Medicine Salt Lake City, Utah [email protected] Ronald G. Victor, MD Associate Director Cedars-Sinai Heart Institute Director, Cedars-Sinai Hypertension Center Los Angeles, California [email protected]

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Lead Authors and Contributors

Wanpen Vongpatanasin, MD Associate Professor of Internal Medicine-Cardiology The University of Texas Southwestern Medical School Dallas, Texas [email protected]

Section IV Pulmonary and Critical Care Medicine Lead Author Sharon I. Rounds, MD Professor of Medicine and of Pathology and Laboratory Medicine Brown Medical School Chief of Pulmonary Critical Care Medicine Providence VA Medical Center Providence, Rhode Island [email protected] Contributors Jason M. Aliotta, MD Assistant Professor of Medicine Division of Biology and Medicine Brown University Providence, Rhode Island [email protected] Brian Casserly, MD Assistant Professor of Medicine Brown University Providence, Rhode Island [email protected] Matthew D. Jankowich, MD Instructor in Medicine Division of Biology and Medicine Brown University Providence, Rhode Island [email protected] F. Dennis McCool, MD Chief, Pulmonary Critical Care Medicine Memorial Hospital of Rhode Island Professor of Medicine Alpert Medical School of Brown University Pawtucket, Rhode Island [email protected]

Section V Preoperative and Postoperative Care Lead Author Kim A. Eagle, MD Albion Walter Hewlett Professor of Internal Medicine Chief, Clinical Cardiovascular Medicine Director, Cardiovascular Center University of Michigan Medical School Ann Arbor, Michigan [email protected]

Contributors Wei C. Lau, MD Clinical Associate Professor Director, Adult Cardiovascular Thoracic Anesthesiology Medical Director, Cardiovascular Center Operating Rooms Department of Anesthesiology University of Michigan Health System Ann Arbor, Michigan [email protected]

Section VI Renal Disease Lead Author Raymond C. Harris, MD Ann and Roscoe R. Robinson Professor of Medicine Director, Division of Nephrology Vanderbilt University School of Medicine Nashville, Tennessee [email protected] Contributors Thomas E. Andreoli, MD, MACP, FRCP (Edinburgh), FRCP (London), ScD (hon.), Docteur (hon.), MD (hon.), Doctor (hon.) Distinguished Professor of Internal Medicine and of Physiology and Biophysics Nolan Chairman Emeritus of Internal Medicine University of Arkansas College of Medicine Little Rock, Arkansas Amanda W. Basford, MD Kidney Associates, PLLC 6624 Fannin, Suite 1400 Houston, Texas [email protected] Kerri L. Cavanaugh, MD Assistant Professor of Medicine Vanderbilt University School of Medicine Nashville, Tennessee [email protected] Jamie P. Dwyer, MD Assistant Professor of Medicine, Nephrology and Hypertension Vanderbilt University School of Medicine Nashville, Tennessee [email protected] Thomas A. Golper, MD Professor of Medicine/Nephrology Director, Medical Specialties Patient Care Center Vanderbilt University School of Medicine Nashville, Tennessee [email protected] Michelle W. Krause, MD, MPH Assistant Professor of Medicine Division of Nephrology Department of Internal Medicine University of Arkansas College of Medicine Little Rock, Arkansas [email protected]

Lead Authors and Contributors T. Alp Ikizler, MD Catherine McLaughlin Hakim Professor of Medicine Director, Clinical Research in Nephrology Director, Master of Science in Clinical Investigation Program Medical Director, Vanderbilt Outpatient Dialysis Unit Division of Nephrology Vanderbilt University School of Medicine Nashville, Tennessee [email protected] Julia B. Lewis, MD Professor of Medicine Director, Fellowship Training Division of Nephrology Vanderbilt University School of Medicine Nashville, Tennessee [email protected] James M. Luther, MD, MSCI Assistant Professor of Medicine Division of Nephrology Vanderbilt University School of Medicine Nashville, Tennessee [email protected] James L. Pirkle, MD Nephrology and Hypertension Specialists, P.C. Dalton, Georgia [email protected] Didier Portilla, MD Professor of Medicine Division of Nephrology Department of Internal Medicine University of Arkansas College of Medicine Little Rock, Arkansas [email protected] Robert L. Safirstein, MD Professor, Executive Vice Chair Department of Internal Medicine University of Arkansas College of Medicine Chief of Medical Services Central Arkansas Veterans Hospital Little Rock, Arkansas [email protected] Gerald Schulman, MD Professor of Medicine Division of Nephrology Vanderbilt University School of Medicine Nashville, Tennessee [email protected] Sudhir V. Shah, MD Professor and Director Division of Nephrology Department of Internal Medicine University of Arkansas College of Medicine Little Rock, Arkansas [email protected]

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Roy Zent, MD Associate Professor of Medicine, Cancer Biology, and Cell and Developmental Biology Division of Nephrology Vanderbilt University School of Medicine Nashville, Tennessee [email protected]

Section VII Gastrointestinal Disease Lead Author M. Michael Wolfe, MD Professor of Medicine Research Professor of Physiology and Biophysics Boston University School of Medicine Chief, Section of Gastroenterology Boston Medical Center Boston, Massachusetts 02118 [email protected] Contributors Wanda P. Blanton, MD Instructor, Department of Medicine Section of Gastroenterology Boston University School of Medicine Boston, Massachusetts [email protected] Charles M. Bliss Jr., MD, FACP Assistant Professor of Medicine Section of Gastroenterology Boston University School of Medicine Boston, Massachusetts [email protected] Francis A. Farraye, MD, MSc Clinical Director, Section of Gastroenterology Co-Director, Center for Digestive Disorders Professor of Medicine Boston University School of Medicine Boston, Massachusetts [email protected] Christopher S. Huang, MD Instructor of Medicine Section of Gastroenterology Boston University School of Medicine Boston, Massachusetts [email protected] Brian C. Jacobson, MD, MPH Director of Endoscopic Ultrasonography Associate Director of Endoscopy Services Boston Medical Center and Assistant Professor of Medicine Boston University School of Medicine Boston, Massachusetts [email protected]

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David R. Lichtenstein, MD, FACG Director of Gastrointestinal Endoscopy Associate Professor of Medicine Boston University School of Medicine Boston, Massachusetts [email protected] Robert Lowe, MD Associate Professor of Medicine Educational Director of the Section of Gastroenterology Boston University School of Medicine Boston, Massachusetts [email protected] Daniel S. Mishkin, MD, CM Director, The Endoscopy Center of Brookline Instructor of Medicine Boston University School of Medicine Boston, Massachusetts [email protected] T. Carlton Moore, MD Assistant Professor in Medicine Section of Gastroenterology Boston University School of Medicne Boston, Massachusetts [email protected] Jaime A. Oviedo, MD, FACG Greater Boston Gastroenterology Framingham, Massachusetts [email protected] Marcos C. Pedrosa, MD, MPH Chief of Endoscopy VA Boston HealthCare System Brigham and Women’s Hospital Boston, Massachusetts [email protected] Elihu M. Schimmel, MD Director VA Advanced Specialty Training Program in Gastroenterology and Hepatology Boston VA Hospital Boston, Massachusetts [email protected] Paul C. Schroy, III, MD, MPH Director of Clinical Research Section of Gastroenterology Associate Professor of Medicine Boston University School of Medicine Associate Professor of Epidemiology/Biostatistics Boston University School of Public Health Boston, Massachusetts [email protected] Satish K. Singh, MD Assistant Professor of Medicine Boston University School of Medicine Staff Gastroenterologist VA Boston HealthCare System Boston, MA 02118 [email protected]

Chi-Chuan Tseng, MD, PhD Associate Professor of Medicine Department of Medicine Boston University School of Medicine Associate Chief Boston Veterans Administration Health Care System Boston, Massachusetts [email protected]

Section VIII Diseases of the Liver and Biliary System Lead Author Michael B. Fallon, MD Professor of Medicine Director, Division of Gastroenterology, Hepatology and Nutrition The University of Texas Medical School Houston, Texas [email protected] Contributors Miguel R. Arguedas MD, MPH Assistant Professor Division of Gastroenterology University of Alabama School of Medicine MCLM 280 Birmingham, Alabama [email protected] Rudolf Garcia-Gallont, MD Head, Department of Surgery Amedesgua Hospital Guatemala City, Guatemala [email protected] Rajan Kochar, MD Assistant Professor of Medicine Division of Gastroenterology, Hepatology and Nutrition The University of Texas Medical School Houston, Texas [email protected] Brendan M. McGuire, MD, MS Associate Professor Medical Director, Liver Transplantation/Medicine Liver Center, Department of Medicine University of Alabama School of Medicine Birmingham, Alabama [email protected] Klaus Mönkemüller, MD Associate Professor Chief, Endoscopy and Outpatient Clinic Division of Gastroenterology, Hepatology and Infectious Diseases Otto-von-Guericke University Magdeburg, Germany [email protected]

Lead Authors and Contributors Helmut Neumann, MD Faculty of Medicine Division of Gastroenterology, Hepatology and Infectious Diseases Otto-von-Guericke University Magdeburg, Germany [email protected] Aasim M. Sheikh, MD Northwest Georgia Gastroenterology Associates Marietta, Georgia [email protected] Shyam Varadarajulu, MD Assistant Professor, Division of Gastroenterology Director, Interventional Endoscopy University of Alabama at Birmingham Birmingham, Alabama [email protected]

Section IX Hematologic Disease Lead Author Nancy Berliner, MD Professor of Medicine Harvard Medical School Chief, Division of Hematology Brigham and Women’s Hospital Boston, Massachusetts [email protected] Contributors Jill Lacy, MD Associate Professor of Medical Oncology Yale University School of Medicine New Haven, Connecticut [email protected] Christine S. Rinder, MD Associate Professor of Anesthesiology and Laboratory Medicine Yale University School of Medicine Department of Anesthesiology Yale-New Haven Hospital New Haven, Connecticut [email protected] Henry M. Rinder, MD Professor of Laboratory Medicine and Internal Medicine Director, Clinical Hematology Laboratory Program Director, Clinical Pathology Residency Training Yale University School of Medicine New Haven, Connecticut [email protected] Michal G. Rose, MD Associate Professor of Medicine Yale University School of Medicine Chief, Cancer Center VA Connecticut HealthCare System New Haven, Connecticut [email protected]

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Stuart E. Seropian, MD Associate Professor of Medicine Yale Cancer Center Lymphoma, Leukemia and Myeloma Program New Haven, Connecticut [email protected] Christopher Tormey, MD Instructor, Laboratory Medicine Yale University School of Medicine New Haven, Connecticut [email protected] Richard Torres, MD Attending Hematopathologist Yale University School of Medicine New Haven, Connecticut [email protected] Eunice S. Wang, MD Research Assistant Professor Leukemia Service, Departments of Medicine and Immunology Staff Physician Leukemia Service Roswell Park Cancer Institute Buffalo, New York [email protected]

Section X Oncologic Disease Lead Author Jennifer J. Griggs, MD, MPH Associate Professor Department of Internal Medicine Division of Hematology/Oncology Director, Breast Cancer Survivorship Program University of Michigan Comprehensive Cancer Center University of Michigan Medical School Ann Arbor, Michigan [email protected] Contributors Barbara A. Burtness, MD Medical Oncologist Fox Chase Cancer Center Philadelphia, Pennsylvania [email protected] Alok A. Khorana, MD, FACP Assistant Professor of Medicine, James P. Wilmot Cancer Center University of Rochester School of Medicine and Dentistry Rochester, New York [email protected] Paula M. Lantz, MD Professor and Chair Department of Health Management and Policy Research Professor, Institute for Social Research University of Michigan Health System Ann Arbor, Michigan [email protected]

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Robert F. Todd, III, MD, PhD Margaret M. Alkek Distinguished Chair and Professor Department of Medicine Baylor College of Medicine Houston, Texas [email protected]

Section XI Metabolic Disease Lead Author Robert J. Smith, MD Director, Division of Endocrinology Director, Hallett Center for Diabetes and Endocrinology Brown University Alpert Medical School Providence, Rhode Island [email protected] Contributors David G. Brooks, MD, PhD Medical Director, Global Clinical Development Abraxis Bioscience, LLC Burlington, Massachusetts [email protected] Geetha Gopalakrishnan, MD Assistant Professor Division of Biology and Medicine Brown University Alpert Medical School Providence, Rhode Island [email protected]

Section XII Endocrine Disease Section Author Glenn D. Braunstein, MD Professor of Medicine UCLA School of Medicine Chair, Department of Medicine Cedars-Sinai Medical Center Los Angeles, California [email protected] Contributors Philip S. Barnett, MD, PhD Director Anna and Max Webb and Family Diabetes Outpatient Treatment and Education Center Cedars Sinai Medical Center Professor of Medicine David Geffen School of Medicine University of California, Los Angeles Los Angeles, California [email protected] Vivien S. Herman-Bonert, MD Associate Professor of Medicine David Geffen School of Medicine Division of Endocrinology University of California, Los Angeles Attending Physician, Cedars Sinai Medical Center Los Angeles, California [email protected]

Osama Hamdy, MD Medical Director Obesity Clinical Program Joslin Diabetes Center Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts [email protected]

Theodore C. Friedman, MD, PhD Associate Professor of Medicine UCLA School of Medicine Endocrinology Division Cedars Sinai Medical Center Los Angeles, California [email protected]

Michelle P. Warren, MD Wyeth-Ayerst Professor Founder and Medical Director Center for Menopause, Hormonal Disorders and Women’s Health Department of Obstetrics and Gynecology Columbia University College of Physicians and Surgeons New York, New York [email protected]

Section XIII Women’s Health

Thomas R. Ziegler, MD Professor of Medicine Atlanta Clinical and Translational Science Institute Emory University School of Medicine Atlanta, Georgia [email protected]

Contributors Patricia I. Carney, MD Department of Obstetrics and Gynecology Christiana Care Health Services Newark, Delaware [email protected]

Lead Author Pamela A. Charney, MD Assistant Professor of Medicine Weill Cornell Medical College New York, New York [email protected]

Lead Authors and Contributors Deborah B. Ehrenthal, MD, FACP Departments of Internal Medicine and Obstetrics and Gynecology Christiana Care Health Services Newark, Delaware Clinical Assistant Professor of Medicine Thomas Jefferson University Philadelphia, Pennsylvania [email protected] Renee K. Kottenhahn, MD Department of Pediatrics Christiana Care Health Services Newark, Delaware [email protected]

Section XIV Men’s Health Lead Author Joseph A. Smith, Jr., MD Professor and Chair Department of Urologic Surgery Vanderbilt University School of Medicine Nashville, Tennessee [email protected] Contributors Douglas F. Milam, MD Associate Professor Department of Urologic Surgery Vanderbilt University School of Medicine Nashville, Tennessee [email protected] Johnathan S. Starkman, MD Clinical Instructor Department of Urologic Surgery Vanderbilt University School of Medicine Nashville, Tennessee [email protected]

Section XV Diseases of Bone and Bone Mineral Metabolism Lead Author Andrew F. Stewart, MD Professor of Medicine Chief, Division of Endocrinology and Metabolism University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected] Contributors Susan L. Greenspan, MD Professor of Medicine Director, Osteoporosis Prevention and Treatment Center Associate Program Director, General Clinical Research Center University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected]

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Steven P. Hodak, MD Clinical Assistant Professor of Medicine Medical Director, Center for Diabetes and Endocrinology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected] Mara J. Horwitz, MD Assistant Professor of Medicine Division of Endocrionology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected] Shane O. LeBeau, MD Clinical Assistant Professor of Medicine Center for Diabetes and Endocrinology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected] G. David Roodman, MD, PhD Professor of Medicine University of Pittsburgh Hillman Cancer Center Pittsburgh, Pennsylvania [email protected]

Section XVI Musculoskeletal and Connective Tissue Disease Lead Author Larry W. Moreland, MD Margaret Jane Miller Endowed Professor of Arthritis Research Chief, Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected] Contributors Surabhi Agarwal, MD Medical Resident University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected] Dana P. Ascherman, MD Assistant Professor of Medicine Divison of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected] Robyn T. Domsic, MD Assistant Professor of Medicine Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected]

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Jennifer Rae Elliott, MD Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected] Amy H. Kao, MD, MPH Assistant Professor of Medicine Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected]

Section XVII Infectious Disease Lead Author Edward J. Wing, MD, FACP, FIDSA Dean of Medicine and Biological Sciences The Warren Alpert Medical School of Brown University Providence, Rhode Island [email protected]

Fotios Koumpouras, MD Assistant Professor of Medicine Medical Director, Lupus Center of Excellence Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected]

Contributors Keith B. Armitage, MD Professor of Medicine Vice Chair for Education Department of Medicine Co-Director, Medicine/Pediatrics Residency Director, Internal Medicine Residency Training Program Case Western Reserve University Cleveland, Ohio [email protected]

C. Kent Kwoh, MD Professor of Medicine Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected]

Curt G. Beckwith, MD Assistant Professor of Medicine Division of Infectious Diseases Brown Medical School Providence, Rhode Island [email protected]

Douglas W. Lienesch, MD Assistant Professor of Medicine Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected]

David A. Bobak, MD Associate Professor Division of Infectious Diseases Case Western Reserve University University Hospitals of Cleveland Cleveland, Ohio [email protected]

Kathleen McKinnon-Maksimowicz, DO Assistant Professor of Medicine Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected] Thomas A. Medsger, Jr., MD Gerald P. Rodnan Professor of Medicine Division of Rheumatology and Clinical Immunology Director, Scleroderma Research Program University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected] Niveditha Mohan, MD Assistant Professor of Medicine Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected]

Jessica K. Fairley, MD Division of Infectious Disease and HIV Medicine Case Western Reserve University Division of Infectious Disease University Hospitals Cleveland, Ohio [email protected] Scott A. Fulton, MD Assistant Professor Division of Infectious Diseases Case Western Reserve University University Hospitals of Cleveland Cleveland, Ohio [email protected] Corrilynn O. Hileman, MD Internal Medicine Infectious Disease Case Western Reserve University Cleveland, Ohio [email protected]

Lead Authors and Contributors Christoph Lange, MD, PhD Medical Clinic Borstel Research Center Borstel, Germany [email protected], [email protected] Michael M. Lederman, MD Scott R. Inkley Professor of Medicine Case Western Reserve University Co-Director, CWRU/University Hospitals of Cleveland Center for AIDS Research Cleveland, Ohio [email protected] Tracy L. Lemonovich, MD Instructor Division of Infectious Diseases and HIV Medicine Case Western Reserve University Cleveland, Ohio [email protected] Michelle V. Lisagaris, MD Assistant Professor Department of Medicine University Hospitals of Cleveland Cleveland, Ohio [email protected] Amy J. Ray, MD Clinical Instructor and Division Chief University Hospitals Richmond Medical Center Infectious Diseases Division University Hospitals, School of Medicine Case Western Reserve University Cleveland, Ohio [email protected] Benigno Rodriguez, MD Assistant Professor Department of Medicine Case Western Reserve University Cleveland, Ohio [email protected] Robert A. Salata, MD Division Chief Division of Infectious Diseases and HIV Medicine Case Western Reserve University Cleveland, Ohio [email protected] Richard R. Watkins, MD, MS Division of Infectious Diseases Akron General Medical Center Akron, Ohio

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Section XVIII Bioterrorism Lead Author Robert W. Bradsher, Jr., MD Richard V. Ebert Professor of Internal Medicine Vice-Chair for Education, Department of Internal Medicine Director, Division of Infectious Diseases University of Arkansas College of Medicine Little Rock, Arkansas [email protected]

Section XIX Neurologic Disease Lead Author Robert C. Griggs, MD, FACP, FAAN Professor of Neurology, Medicine, Pathology and Laboratory Medicine, and Pediatrics University of Rochester School of Medicine and Dentistry Rochester, New York [email protected] Contributors Michel J. Berg, MD Associate Professor of Neurology and Medical Director, Strong Epilepsy Center University of Rochester School of Medicine and Dentistry Rochester, New York [email protected] Emma Ciafaloni, MD Associate Professor Department of Neurology (SMD) University of Rochester School of Medicine and Dentistry Rochester, New York [email protected] Timothy J. Counihan, MD, MRCPI Department of Neurology Galway University Hospital Galway, Ireland [email protected] William P. Cheshire Jr., MD Professor of Neurology Mayo Clinic Jacksonville, Florida [email protected] Emily C. de los Reyes, MD Associate Professor of Clinical Pediatrics and Neurology Nationwide Children’s Hospital The Ohio State University Columbus, Ohio [email protected]

xviii


Jennifer J. Griggs, MD, MPH Associate Professor Department of Internal Medicine Division of Hematology/Oncology Director, Breast Cancer Survivorship Program University of Michigan Comprehensive Cancer Center University of Michigan Medical School Ann Arbor, Michigan [email protected] Carlayne E. Jackson, MD Professor of Neurology University of Texas Medical School San Antonio, Texas [email protected] Kevin A. Kerber, MD Assistant Professor Department of Neurology Director, Dizziness Clinic University of Michigan Medical School Ann Arbor, Michigan [email protected] Lynn C. Liu, MD Chief, Strong Sleep Disorders Center Department of Neurology University of Rochester School of Medicine and Dentistry Rochester, New York [email protected] Geoffrey S.F. Ling, MD, PhD Defense Advanced Research Projects Agency Defense Sciences Office Arlington, Virginia [email protected] Jeffery M. Lyness, MD Professor and Associate Chair for Education Department of Psychiatry Director of Curriculum, Office of Curriculum and Assessment University of Rochester School of Medicine and Dentistry Rochester, New York [email protected] Deborah Joanne Lynn, MD Associate Professor The Ohio State University Department of Neurology Director, Department of Neurology Medical Student Education Staff Neurologist The Ohio State University Medical Center and The Arthur James Cancer Hospital and Research Institute Co-director, Ohio State University Multiple Sclerosis Center Columbus, Ohio [email protected] Frederick J. Marshall, MD Associate Professor Department of Neurology (SMD) University of Rochester Rochester, New York [email protected]

Allan McCarthy, MD, MRCPI Department of Neurology Galway University Hospital Galway, Ireland [email protected] Sinéad M. Murphy, BA, MB, BCh, MRCPI Department of Neurology Galway University Hospital Galway, Ireland [email protected] Avindra Nath, MD Professor of Neurology Johns Hopkins University Baltimore, Maryland [email protected] E. Steve Roach, MD Vice Chair for Clinical Affairs Department of Pediatrics Director, Division of Pediatric Neurology Professor of Child Neurology Nationwide Children’s Hospital The Ohio State University Columbus, Ohio [email protected] Lisa R. Rogers, DO Director, Medical Neuro-Oncology University Hospitals—Case Medical Center and Professor of Neurology Department of Neurology Case Western University School of Medicine Cleveland, Ohio [email protected] Roger P. Simon, MD Chair and Director R.S. Dow Neurobiology Laboratories Legacy Research Hospital and Adjunct Professor Neurology, Physiology and Pharmacology Oregon Health and Science University Portland, Oregon [email protected]

Section XX The Aging Patient Lead Author Harvey J. Cohen, MD Walter Kempner Professor and Chair of Medicine Director, Center for the Study of Aging and Human Development Duke University School of Medicine Durham, North Carolina [email protected]


xix

Contributor Mitchell T. Heflin, MD, MHS Assistant Professor of Medicine and Geriatrics Center for the Study of Aging and Human Development Duke University School of Medicine Durham, NC Durham, North Carolina [email protected]

Section XXII Alcohol and Substance Abuse

Section XXI Palliative Care

Richard A. Lange, MD Professor and Executive Vice-Chair Department of Medicine University of Texas Medical School San Antonio, Texas [email protected]

Lead Authors Timothy E. Quill, MD Professor of Medicine, Psychiatry and Medical Humanities Director, Palliative Care Program University of Rochester School of Medicine Rochester, New York [email protected] Robert G. Holloway, MD, MPH Professor, Department of Neurology Professor, Department of Community and Preventive Medicine (SMD) Rochester, New York [email protected]

Lead Authors L. David Hillis, MD Dan Parman Distinguished Professor Chair, Department of Internal Medicine University of Texas Medical School San Antonio, Texas [email protected]


Preface This is the eighth edition of Andreoli and Carpenter’s Cecil Essentials of Medicine. Essentials VIII, like its predecessors, is intended to be comprehensive but concise. Essentials VIII therefore provides an exacting and thoroughly updated treatise on internal medicine, without excessive length, for students of medicine at all levels of their careers. We welcome with enthusiasm a new editor, Edward J. Wing, MD, Frank L. Day Professor of Biology, and Dean of Medicine and Biological Sciences at Brown University Warren Alpert Medical School. Essentials VIII has three cardinal components. First, at the beginning of each section—kidney, for example—we provide a brief but rigorous summary of the fundamental biology of the kidney and/or the cardinal signs and symptoms of diseases of the kidney. The same format has been used in all the sections of the book. Second, the main body of each section contains a detailed, but again, concise description of the diseases of the various organ systems, together with their pathophysiology and their treatment. Finally, Essentials relies heavily on the Internet. Essentials VIII is published entirely on a Web site on the Internet. In the online version of Essentials VIII, we provide a substantial amount of supplemental material, indicated in the hard copy text by boldface symbols (for example, Web Fig. 1) and

denoted by an arrow icon shown in the margin of this page. This icon is present throughout the hard copy of the book as well as in the Internet version and directs the reader to a series of illustrations, tables, or videos in the Internet version of Essentials. This material is clearly crucial to understanding modern medicine, but we hope that, in this manner, the supplemental material will enrich Essentials VIII without having enlarged the book significantly. As in prior editions, we make abundant use of 4-color illustrations. And as in prior editions, each section has been reviewed by one or another of the editors, and finally by the editor-in-chief. We thank James T. Merritt, Senior Acquisitions Editor, Medical Education, of Elsevier, Inc., and especially Rebecca Gruliow, Managing Editor for Global Medicine, Elsevier, Inc. Both Jim Merritt and Rebecca Gruliow contributed heartily to the preparation of this eighth edition of Essentials. Lastly, we thank our very able secretarial staff, Ms. Clementine M. Whitman (Little Rock); Ms. Barbara S. Bottone (Providence); Ms. Shirley E. Thomas (Rochester); Ms. Jennifer F. Schroff (Salt Lake City); and Ms. Jean M. Drinan, and Ms. Catarina A. Santos (Providence). The Editors

xxi


Contents SECTION I

Introduction to Molecular Medicine

1

1 Molecular Basis of Human Disease

2

Ivor J. Benjamin

2 Evidence-Based Medicine, Quality of Life, and the Cost of Medicine Sara G. Tariq and Susan S. Beland

15 16

SECTION III

Cardiovascular Disease

3 Structure and Function of the Normal Heart and Blood Vessels Jack Morshedzadeh, Dean Y. Li and Ivor J. Benjamin

4 Evaluation of the Patient with Cardiovascular Disease

Sheldon E. Litwin and Ivor J. Benjamin

192

16 Evaluating Lung Structure and Function

198

17 Obstructive Lung Diseases

213

18 Interstitial Lung Diseases

225

19 Pulmonary Vascular Disease

241

20 Disorders of Respiratory Control

245

21 Disorders of the Pleura, Mediastinum, and Chest Wall

248

22 Infectious Diseases of the Lung

254

23 Essentials In Critical Care Medicine

259

24 Neoplastic Disorders of the Lung

266

Brian Casserly and Sharon Rounds

F. Dennis McCool

SECTION II

Evidence-Based Medicine

15 General Approach to Patients with Respiratory Disorders

21 22

Matthew D. Jankowich Jason M. Aliotta and Matthew D. Jankowich Sharon Rounds

Sharon Rounds and Matthew D. Jankowich

F. Dennis McCool

32

Brian Casserly and Sharon Rounds

5 Diagnostic Tests and Procedures in the Patient with Cardiovascular Disease

46

6 Heart Failure and Cardiomyopathy

66

7 Congenital Heart Disease

75

8 Acquired Valvular Heart Disease

84

Preoperative and Postoperative Care

273

9 Coronary Heart Disease

95

25 Preoperative and Postoperative Care

274

Sheldon E. Litwin

Sheldon E. Litwin and Ivor J. Benjamin Kevin J. Whitehead Sheldon E. Litwin

Andrew D. Michaels

Brian Casserly and Sharon Rounds Matthew D. Jankowich and Jason M. Aliotta

SECTION V

Wel C. Lau and Kim A. Eagle

10 Cardiac Arrhythmias

118

11 Pericardial and Myocardial Disease

145

Renal Disease

12 Other Cardiac Topics

156

26 Elements of Renal Structure and Function

286

27 Approach to the Patient with Renal Disease

298

28 Fluid and Electrolyte Disorders

305

29 Glomerular Diseases

323

Mohamed H. Hamdan

Josef Stehlik and Ivor J. Benjamin

David A. Bull and Ivor J. Benjamin

13 Vascular Diseases and Hypertension Wanpen Vongpatanasin and Ronald G. Victor

Robert L. Safirstein

165

Michelle W. Krause, Thomas A. Golper, Raymond C. Harris and Sudhir V. Shah

SECTION IV

Pulmonary and Critical Care Medicine

187

14 The Lung in Health and Disease

188

Sharon Rounds and Matthew D. Jankowich

SECTION VI

Thomas E. Andreoli and Robert L. Safirstein

Jamie P. Dwyer and Julia B. Lewis

xxiii

xxiv

Contents

30 Major Nonglomerular Disorders

333

44 Fulminant Hepatic Failure

476

31 Vascular Disorders of the Kidney

345

45 Cirrhosis of the Liver and its Complications

478

46 Disorders of the Gallbladder and Biliary Tract

488

James L. Pirkle, Amanda W. Basford and Roy Zent James M. Luther and Gerald Schulman

32 Acute Kidney Injury

359

33 Chronic Renal Failure

369

Didier Portilla and Sudhir V. Shah Kerri Cavanaugh and T. Alp Ikizler

Rajan Kochar, Miguel R. Arguedas and Michael B. Fallon

Shyam Varadarajulu, Rudolf Garcia-Gallont and Michael B. Fallon

SECTION VII

Gastrointestinal Disease

Brendan M. McGuire and Michael B. Fallon

381

SECTION IX

34 Common Clinical Manifestations of Gastrointestinal Disease

382

Hematologic Disease

495

A. Abdominal Pain

382

496

B. Gastrointestinal Hemorrhage

385

47 Hematopoiesis and Hematopoietic Failure

48 Clonal Disorders of the Hematopoietic Stem Cell

507

49 Disorders of Red Blood Cells

520

50 Clinical Disorders of Neutrophils

533

51 Disorders of Lymphocytes

539

52 Normal Hemostasis

555

53 Disorders of Hemostasis: Bleeding

564

54 Disorders of Hemostasis: Thrombosis

580

Charles M. Bliss, Jr. and M. Michael Wolfe T. Carlton Moore, Chi-Chuan Tseng and M. Michael Wolfe

C. Malabsorption

389

D. Diarrhea

396

35 Endoscopic and Imaging Procedures

401

36 Esophageal Disorders

408

Marcos C. Pedrosa and Elihu M. Schimmel Satish K. Singh Brian C. Jacobson and Daniel S. Mishkin Robert C. Lowe and M. Michael Wolfe

37 Diseases of the Stomach and Duodenum

Wanda P. Blanton, Jaime A. Oviedo and M. Michael Wolfe

38 Inflammatory Bowel Disease Christopher S. Huang and Francis A. Farraye

414

Michal G. Rose and Nancy Berliner Michal G. Rose and Nancy Berliner Jill Lacy and Stuart Seropian

Christopher A. Tormey and Henry M. Rinder

430

Richard Torres and Henry M. Rinder

439

40 Diseases of the Pancreas

445

David R. Lichtenstein

Eunice S. Wang and Nancy Berliner

Christine S. Rinder and Henry M. Rinder

39 Neoplasms of the Gastrointestinal Tract Paul C. Schroy III

Eunice S. Wang and Nancy Berliner

SECTION VIII

SECTION X

Oncologic Disease

593

55 Cancer Biology and Etiologic Factors

594

Diseases of the Liver and Biliary System

455

Alok A. Khorana and Barbara A. Burtness

41 Laboratory Tests in Liver Disease

456

56 Cancer Epidemiology and Cancer Prevention

598

57 Solid Tumors

603

58 Complications of Cancer and Cancer Treatment

616

Rajan Kochar and Michael B. Fallon

42 Jaundice

Klaus Mönkemüller, Helmut Neumann and Michael B. Fallon

43 Acute and Chronic Hepatitis

Rajan Kochar, Aasim M. Sheikh and Michael B. Fallon

460

Paula M. Lantz and Jennifer J. Griggs Robert F. Todd lll and Jennifer J. Griggs

466

Alok A. Khorana and Jennifer J. Griggs

Contents

59 Principles of Cancer Therapy Alok A. Khorana and Barbara A. Burtness

621

SECTION XI

Metabolic Disease

629

60 Obesity

630

Osama Hamdy and Robert J. Smith

61 Anorexia Nervosa and Bulimia Nervosa Michelle P. Warren

635

62 Malnutrition, Nutritional Assessment, and Nutritional Support in Adult Patients

638

63 Disorders of Lipid Metabolism

643

Thomas R. Ziegler

Geetha Gopalakrishnan and Robert J. Smith

64 Disorders of Metals and Metalloproteins David G. Brooks

651

SECTION XIV

Men’s Health

751

72 Men’s Health Topics

752

A. Benign Prostatic Hyperplasia

752

B. Prostatitis

757

C. Erectile Dysfunction

759

D. Carcinomas of Men

763

E. Benign Scrotal Diseases

768

Jonathan S. Starkman, Douglas F. Milam and Joseph A. Smith, Jr.

SECTION XV

Diseases of Bone and Bone Mineral Metabolism

771

73 Normal Physiology of Bone and Mineral Homeostasis

772

74 Disorders of Serum Minerals

783

75 Metabolic Bone Diseases

795

Andrew F. Stewart

Steven P. Hodak and Andrew F. Stewart

SECTION XII

xxv

Endocrine Disease

659

65 Hypothalamic-Pituitary Axis

660

76 Osteoporosis

802

66 Thyroid Gland

670

77 Paget Disease of Bone

811

67 Adrenal Gland

679

68 Male Reproductive Endocrinology

691

69 Diabetes Mellitus

697

70 Hypoglycemia

721

Vivien S. Herman-Bonert

Vivien S. Herman-Bonert and Theodore C. Friedman Theodore C. Friedman Glenn D. Braunstein

Philip S. Barnett and Glenn D. Braunstein Philip S. Barnett

Shane O. LeBeau and Andrew F. Stewart Susan L. Greenspan Mara J. Horwitz and G. David Roodman

SECTION XVI

Musculoskeletal and Connective Tissue Disease

817

78 Approach to the Patient with Rheumatic Disease

818

79 Rheumatoid Arthritis

823

80 Spondyloarthropathies

829

Niveditha Mohan

Larry W. Moreland

Douglas W. Lienesch

SECTION XIII

Women’s Health

729

81 Systemic Lupus Erythematosus

834

71 Women’s Health Topics

730

82 Antiphospholipid Antibody Syndrome

841

A. Introduction

730

83 Systemic Sclerosis (Scleroderma)

844

B. Preventive Health Recommendations for Women

733

84 Idiopathic Inflammatory Myopathies

850

C. Health Issues Across the Life Course

734

D. Special Topics

745

85 Sjögren Syndrome

855

Deborah Ehrenthal, Patricia Carney, Renee Kottenhahn and Pamela Charney

Jennifer Rae Elliot

Surabhi Agarwal and Amy H. Kao Robyn T. Domsic and Thomas A. Medsger, Jr. Larry W. Moreland

Fotios Koumpouras

xxvi

Contents

86 Systemic Vasculitis

858

87 Crystal Arthropathies

864

88 Osteoarthritis

870

89 Nonarticular Soft Tissue Disorders

873

Kathleen Maksimowicz-Mckinnon Dana P. Ascherman C. Kent Kwoh

Niveditha Mohan

90 Rheumatic Manifestations of Systemic Disorders Fotios Koumpouras

878

883

91 Organisms that Infect Humans

884

Benigno Rodríguez and Michael M. Lederman

890

93 Laboratory Diagnosis of Infectious Diseases

898

94 Antimicrobial Therapy

904

Benigno Rodríguez and Michael M. Lederman Benigno Rodríguez and Michael M. Lederman

95 Fever and Febrile Syndromes

910

96 Bacteremia and Sepsis Syndrome

925

97 Infections of the Nervous System

933

98 Infections of the Head and Neck

945

Tracy L. Lemonovich and Robert A. Salata Richard R. Watkins and Robert A. Salata Scott A. Fulton and Robert A. Salata Christoph Lange and Michael M. Lederman

99 Infections of the Lower Respiratory Tract Christoph Lange and Michael M. Lederman

100 Infections of the Heart and Blood Vessels Benigno Rodríguez and Michael M. Lederman

101 Skin and Soft Tissue Infections Christoph Lange and Michael M. Lederman

102 Intra-Abdominal Abscess and Peritonitis Christoph Lange and Michael M. Lederman

104 Infections Involving Bones and Joints

985

105 Infections of the Urinary Tract

989

106 Health Care−Associated Infections

992

107 Sexually Transmitted Infections

998

108 Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome

1008

109 Infections in the Immunocompromised Host

1028

110 Infectious Diseases of Travelers: Protozoal and Helminthic Infections

1034

Christoph Lange and Michael M. Lederman

Amy J. Ray, Michelle V. Lisgaris and Robert A. Salata

Infectious Disease

92 Host Defenses Against Infection

979



SECTION XVII

Benigno Rodríguez and Michael M. Lederman

103 Infectious Diarrhea

Corrilynn O. Hileman, Keith B. Armitage and Robert A. Salata

Curt G. Beckwith, Edward J. Wing, Benigno Rodríguez and Michael M. Lederman

Tracy Lemonovich, David A. Bobak and Robert A. Salata

Jessica K. Fairley, Keith B. Armitage and Robert A. Salata

SECTION XVIII

951

Bioterrorism

1043

111 Bioterrorism

1044

Robert W. Bradsher, Jr.

SECTION XIX

Neurologic Disease

1051

112 Neurologic Evaluation of the Patient

1052

113 Disorders of Consciousness

1058

114 Disorders of Sleep

1064

115 Cortical Syndromes

1068

116 Dementia and Memory Disturbances

1072

117 Major Disorders of Mood, Thoughts, and Behavior

1077

Frederick J. Marshall Roger P. Simon

961

969

Lynn Liu

Sinéad M. Murphy and Timothy J. Counihan Frederick J. Marshall

975

Jeffrey M. Lyness

Contents

118 Disorders of Thermal Regulation William P. Cheshire, Jr.

119 Headache, Neck Pain, and Other Painful Disorders Timothy J. Counihan

120 Disorders of Vision and Hearing

Allan McCarthy and Timothy J. Counihan

1083

1086 1096

121 Dizziness and Vertigo

1104

122 Disorders of the Motor System

1108

123 Developmental and Neurocutaneous Disorders

1119

124 Cerebrovascular Disease

1123

Kevin A. Kerber

Frederick J. Marshall

Emily C. de los Reyes and E. Steve Roach Sinéad M. Murphy and Timothy J. Counihan

125 Traumatic Brain Injury and Spinal Cord Injury Geoffrey S. F. Ling

1136

xxvii

130 Neuromuscular Diseases: Disorders of the Motor Neuron and Plexus and Peripheral Nerve Disease

1171

131 Muscle Diseases

1182

132 Neuromuscular Junction Disease

1191

Carlayne E. Jackson Robert C. Griggs Emma Ciafaloni

SECTION XX

The Aging Patient

1195

133 The Aging Patient

1196

Mitchell T. Heflin and Harvey Jay Cohen

SECTION XXI

Palliative Care

1209

134 Palliative Care

1210

Robert G. Holloway and Timothy E. Quill

SECTION XXII

126 Epilepsy

1141

Alcohol and Substance Abuse

1219

127 Central Nervous System Tumors

1154

135 Alcohol and Substance Abuse

1220

128 Infectious Diseases of the Nervous System

1159

Index

1235

129 Demyelinating and Inflammatory Disorders

1165

Michel J. Berg Lisa R. Rogers and Jennifer J. Griggs

Avindra Nath

Deborah Joanne Lynn

Richard A. Lange and L. David Hillis


Section I Introduction to Molecular Medicine

1

Molecular Basis of Human Disease –

BENJAMIN

I

Chapter

1

Molecular Basis of Human Disease Ivor J. Benjamin

M

edicine has evolved dramatically during the past century from a healing art in which standards of practice were established on the basis of personal experience, passed on from one practitioner to the next, to a rigorous intellectual discipline steeped in the scientific method. The scientific method, a process that tests the validity of a hypothesis or prediction through experimentation, has led to major advances in the fields of physiology, microbiology, biochemistry, and pharmacology. These advances served as the basis for the diagnostic and therapeutic approaches to illness in common use by physicians through most of the 20th century. Since the 1980s, the understanding of the molecular basis of genetics has expanded dramatically, and advances in this field have identified new and exciting dimensions for defining the basis of conventional genetic diseases (e.g., sickle cell disease) as well as the basis of complex genetic traits (e.g., hypertension). The molecular basis for the interaction between genes and environment has also begun to be defined. Armed with a variety of sensitive and specific molecular techniques, contemporary physicians can now begin not only to understand the molecular underpinning of complex pathobiologic processes but also to identify individuals at risk for common diseases. Understanding modern medicine, therefore, requires an understanding of molecular genetics and the molecular basis of disease. This introductory chapter offers an overview of this complex and rapidly evolving topic and attempts to summarize the principles of molecular medicine that will be highlighted in specific sections throughout this text.

Deoxyribonucleic Acid and the Genome All organisms possess a scheme to transmit the essential information containing the genetic make-up of the species through successive generations. In human cells, 23 pairs of chromosomes are present, each pair of which contains a 2

unique sequence and therefore unique genetic information. In the human genome, about 6 × 109 nucleotides, or 3 × 109 pairs of nucleotides, associate in the double helix. All the specificity of DNA is determined by the base sequence, and this sequence is stored in complementary form in the double-helical structure, which facilitates correction of sequence errors and provides a mechanistic basis for replication of the information during cell division. Each DNA strand serves as a template for replication, which is accomplished by the action of DNA-dependent polymerases that unwind the double-helical DNA and copy each single strand with remarkable fidelity. All cell types except for gametocytes contain this duplicate, diploid number of genetic units, one half of which is referred to as a haploid number. The genetic information contained in chromosomes is separated into discrete functional elements known as genes. A gene is defined as a unit of base sequence that usually, but with rare exceptions, encodes a specific polypeptide sequence. New evidence suggests that small, noncoding RNAs play critical roles in expression of this essential information. An estimated 30,000 genes are present in the human haploid genome, and these are interspersed among regions of sequence that do not code for protein and whose function is as yet unknown. For example, noncoding RNAs (e.g., transfer RNA [tRNA], ribosomal RNA [rRNA], and other small RNAs) act as components of enzyme complexes such as the ribosome and spliceosome. The average chromosome contains 3000 to 5000 genes, and these range in size from about 1 kilobase (kb) to 2 megabases (Mb).

Ribonucleic Acid Synthesis Transcription, or RNA synthesis, is the process for transferring information contained in nuclear DNA to an intermediate molecular species known as messenger RNA (mRNA).

Chapter 1—Molecular Basis of Human Disease

Enhancer Silencer

RNA polymerase

Exon 5'

3

Intron

Exon

Intron 3'

Promoter region Transcription start site

Figure 1-1 Transcription. Genomic DNA is shown with enhancer and silencer sites located 5′ upstream of the promoter region, to which RNA polymerase is bound. The transcription start site is shown downstream of the promoter region, and this site is followed by exonic sequences interrupted by intronic sequences. The former sequences are transcribed ad seriatim (i.e., one after another) by the RNA polymerase.

Two biochemical differences distinguish RNA from DNA: (1) the polymeric backbone is made up of ribose rather than deoxyribose sugars linked by phosphodiester bonds, and (2) the base composition is different in that uracil is substituted for thymine. RNA synthesis from a DNA template is performed by three types of DNA-dependent RNA polymerases, each a multi-subunit complex with distinct nuclear location and substrate specificity. RNA polymerase I, located in the nucleolus, directs the transcription of genes encoding the 18S, 5.8S, and 28S ribosomal RNAs, forming a molecular scaffold with both catalytic and structural functions within the ribosome. RNA polymerase II, located in the nucleoplasm instead of the nucleoli, primarily transcribes precursor mRNA transcripts and small RNA molecules. The carboxyl-terminus of RNA polymerase II is uniquely modified with a 220-kD protein domain, the site of enzymatic regulation by protein phosphorylation of critical serine and threonine residues. All tRNA precursors and other rRNA molecules are synthesized by RNA polymerase III in the nucleoplasm. RNA polymerases are synthesized from precursor trans cripts that must first be cleaved into subunits before further processing and assembling with ribosomal proteins into macromolecular complexes. Ribosomal architectural and structural integrity are derived from the secondary and tertiary structures of rRNA, which assume a series of folding patterns containing short duplex regions. Precursors of tRNA in the nucleus undergo the removal of the 5′ leader region, splicing of an internal intron sequences, and modification of terminal residues. Precursors of mRNA are produced in the nucleus by the action of DNA-dependent RNA polymerase II, which copies the antisense strand of the DNA double helix to synthesize a single strand of mRNA that is identical to the sense strand of the DNA double helix in a process called transcription (Fig. 1-1). The initial, immature mRNA first undergoes modification at both the 5′ and 3′ ends. A special nucleotide structure called the cap is added to the 5′ end, which functions to increase binding to the ribosome and enhance translational efficiency. The 3′ end undergoes modification by nuclease cleavage of about 20 nucleotides, followed by the addition of a length of polynucleotide sequence containing a uniform stretch of adenine bases, the so-called poly A tail that stabilizes the mRNA. In addition to these changes that uniformly occur in all mRNAs, other, more selective modifications can also occur.

MET CYS

PRO

THR

Anticodon GGG

UGC AUG

UCG

ACG Codon

CCC

UCG

AUU

GUA

Open reading frame

Figure 1-2 Translation. The open reading frame of a mature messenger RNA is shown with its series of codons. Transfer RNA molecules are shown with their corresponding anticodons, charged with their specific amino acid. A short, growing polypeptide chain is depicted. A, adenine; C, cytosine; CYS, cysteine; G, guanine; MET, methionine; PRO, proline; THR, threonine; U, uracil.

Because each gene contains both exonic and intronic sequences and the precursor mRNA is transcribed without regard for exon-intron boundaries, this immature message must be edited in such a way that splices all exons together in appropriate sequence. The process of splicing, or removing intronic sequences to produce the mature mRNA, is an exquisitely choreographed event that involves the intermediate formation of a spliceosome, a large complex consisting of small nuclear RNAs and specific proteins, which contains a loop or lariat-like structure that includes the intron targeted for removal. Only after splicing, a catalytic process requiring adenosine triphosphate hydrolysis, has concluded is the mature mRNA able to transit from the nucleus into the cytoplasm, where the encoded information is translated into protein. Alternative splicing is a process for efficiently generating multiple gene products often dictated by tissue specificity, developmental expression, and pathologic state. Gene splicing allows the expression of multiple isoforms by expanding the repertoire for molecular diversity. An estimated 30% of genetic diseases in humans arise from defects in splicing. The resulting mature mRNA then exits the nucleus to begin the process of translation or conversion of the base code to polypeptide (Fig. 1-2). Alternative splicing pathways (i.e., alternative exonic assembly pathways) for specific genes also serve at the level of transcriptional regulation. The discovery of catalytic RNA, the capacity for self-directed internal

4

Section I—Introduction to Molecular Medicine 3' OH A C C Phosphorylated 5' terminus

Amino acid– attachment site

5' p

TψC loop

DHU loop U

A

G

UH2

G

C T Ψ

C

G "Extra arm" (variable)

U

Anticodon loop

Figure 1-3 Secondary structure of transfer RNA (tRNA). The structure of each tRNA serves as an adapter molecule that recognizes a specific codon for the amino acid to be added to the polypeptide chain. About one half the hydrogen-bonded bases of the single chain of ribonucleotides are shown paired in double helices like a cloverleaf. The 5′ terminus is phosphorylated, and the 3′ terminus contains the hydroxyl group on an attached amino acid. The anticodon loop is typically located in the middle of the tRNA molecule. C, cytocide; DHU, dihydroxyuridine; G, guanine; UH2, dihydrouridine; ψ, pseudouridine; T, ribothymidine; U, uracil. (Data from Berg JM, Tymoczko JL, Strayer JL: Berg, Tymoczko and Stryer’s Biochemistry, 5th ed. New York, WH Freeman, 2006.)

excision and repair, has advanced the current view that RNA per se serves both as a template for translation of the genetic code and, simultaneously, as an enzyme (see “Transcriptional Regulation” later in this chapter). Protein synthesis, or translation of the mRNA code, occurs on ribosomes, which are macromolecular complexes of proteins and rRNA located in the cytoplasm. Translation involves the conversion of the linear code of a triplet of bases (i.e., the codon) into the corresponding amino acid. A fourbase code generates 64 possible triplet combinations (4 × 4 × 4), and these correspond to 20 different amino acids, many of which are encoded by more than one base triplet. To decode mRNA, an adapter molecule (tRNA) recognizes the codon in mRNA through complementary base pairing with a three-base anticodon that it bears; in addition, each tRNA is charged with a unique amino acid that corresponds to the anticodon (Fig. 1-3). Translation on the mRNA template proceeds without punctuation of the non-overlapping code with the aid of rRNA on an assembly machine, termed ribosomes—essen-

tially a polypeptide polymerase. At least one tRNA molecule exists for each 20 amino acids, although degeneracy in the code expands the number of available tRNA molecules, mitigates the chances of premature chain termination, and ameliorates the potential deleterious consequences of single-base mutations. The enzymatic activity of the ribosome then links amino acids through the synthesis of a peptide bond, releasing the tRNA in the process. Consecutive linkage of amino acids in the growing polypeptide chain represents the terminal event in the conversion of information contained within the nuclear DNA sequence into mature protein (DNA → RNA → protein). Proteins are directly responsible for the form and function of an organism. Thus, abnormalities in protein structure or function brought about by changes in primary amino acid sequence are the immediate precedent cause of changes in phenotype, adverse forms of which define a disease state. Inhibition of RNA synthesis is a well-recognized mechanism of specific toxins and antibiotics. Toxicity from the ingestion of the poisonous mushroom (Amanita phalloides), for example, leads to the release of the toxin α-amanitin, a cyclic octapeptide that inhibits the RNA Pol II and blocks elongation of RNA synthesis. The antibiotic actinomycin D binds with high affinity to double-helical DNA and inter colates between base pairs, precluding access of DNAdependent RNA polymerases and the selective inhibition of transcription. Several major antibiotics function through inhibition of translation. For example, the aminoglycoside antibiotics function through the disruption of the mRNAtRNA codon-anticodon interaction, whereas erythromycin and chloramphenicol inhibit peptide bond formation.

Control of Gene Expression OVERVIEW The timing, duration, localization, and magnitude of gene expression are all important elements in the complex tapestry of cell form and function governed by the genome. Gene expression represents the flow of information from the DNA template into mRNA transcripts and the process of translation into mature protein. Four levels of organization involving transcription factors, RNAs, chromatin structure, and epigenetic factors are increasingly recognized to orchestrate gene expression in the mammalian genome. Transcriptional regulators bind to specific DNA motifs that positively or negatively control the expression of neighboring genes. The information contained in the genome must be transformed into functional units of either RNA or protein products. How DNA is packed and modified represents additional modes of gene regulation by disrupting the access of transcription factors from DNAbinding motifs. In the postgenomic era, the challenge is to understand the architecture by which the genome is organized, controlled, and modulated. Transcription factors, chromatin architecture, and modifications of nucleosomal organization make up the major mechanisms of gene regulation in the genome.


TRANSCRIPTIONAL REGULATION The principal regulatory step in gene expression occurs at the level of gene transcription. A specific DNA-dependent RNA polymerase performs the transcription of information contained in genomic DNA into mRNA transcripts. Trans cription begins at a proximal (i.e., toward the 5′ end of the gene) transcription start site, containing nucleotide sequences that influence the rate and extent of the process (see Fig. 1-1). This region is known as the promoter region of the gene and often includes an element of sequence rich in adenine and thymine (the TATA box) along with other sequence motifs within about 100 bases of the start site. These regions of DNA that regulate transcription are known as cis-acting regulatory elements. Some of these regulatory regions of promoter sequence bind proteins known as transacting factors, or transcription factors, which are themselves encoded by other genes. The cis-acting regulatory sequences to which transcription factors bind are often referred to as response elements. Families of transcription factors have been identified and are often described by unique aspects of their predicted protein secondary structure, including helix-turnhelix motifs, zinc-finger motifs, and leucine-zipper motifs. Transcription factors make up an estimated 3% to 5% of the protein-coding products of the genome. In addition to gene-promoter regions, enhancer sites are distinct from promoter sites in that they can exist at distances quite remote from the start site, either upstream or downstream (i.e., beyond the 3′ end of the gene), and without clear orientation requirements. Trans-acting factors bind to these enhancer sites and are believed to alter the tertiary structure or conformation of the DNA in a manner that facilitates the binding and assembly of the transcription-initiation complex at the promoter region, perhaps in some cases by forming a broad loop of DNA in the process. Biochemical modification of select promoter or enhancer sequences, such as methylation of CpG-rich sequences (cytosine-phosphate-guanine), can also modulate transcription; methylation typically suppresses transcription. The terms silencer and suppressor elements refer to cis-acting nucleotide sequences that reduce or shut off gene transcription and do so through association with trans-acting factors that recognize these specific sequences. Regulation of transcription is a complex process that occurs at several levels; importantly, the expression of many genes is regulated to maintain high basal levels, which are known as housekeeping or constitutively expressed genes. They typically yield protein products that are essential for normal cell function or survival and thus must be maintained at a specific steady-state concentration under all circumstances. Many other genes, in contrast, are not expressed or are only modestly expressed under basal conditions; however, with the imposition of some stress or exposure of the cell to an agonist that elicits a cellular response distinct from that of the basal state, the expression of these genes is induced or enhanced. For example, the heat shock protein genes encoding stress proteins are rapidly induced in response to diverse pathophysiologic stimuli (e.g., oxidative stress, heavy metals, inflammation) in most cells and organisms. The increased heat shock protein expression is complementary to the basal level of heat shock proteins whose functions as molecular chaperones play key roles during protein synthesis to prevent protein misfolding, increase protein translocation, and

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accelerate protein degradation. These adaptive responses often mediate changes in phenotype that are homeostatically protective to the cell or organism.

MICRORNAS AND GENE REGULATION Less is currently known about the determinants of translational regulation than is known about transcriptional regulation. The recent discovery and identification of small RNAs (21 to 24 mer), termed microRNAs (miRNAs), adds further complexity to the regulation of gene expression within the eukaryotic genome. First discovered in worms more than 10 years ago, miRNAs are conserved noncoding strands of RNA that bind to the 3′-untranslated regions of target mRNAs, enabling gene silencing of protein expression at the translational level. Gene-encoding miRNAs exhibit tissue-specific expression and are interspersed in regions of the genome unrelated to known genes. Transcription of miRNAs proceeds in multiple steps from sites under the control of an mRNA promoter. RNA polymerase II transcribes the precursor miRNA, termed primary miRNA (primiRNA), containing 5′ caps and 3′ poly (A) tails. In the nucleus, the larger primiRNAs of 70 nucleotides form an internal hairpin loop, embedding the miRNA portion that undergoes recognition and subsequent excision by double-stranded RNA-specific ribonuclease, termed Drosha. Gene expression is silenced by the effect of miRNA on nascent RNA molecules targeted for degradation. Because translation occurs at a fairly invariant rate among all mRNA species, the stability or half-life of a specific mRNA also serves as another point of regulation of gene expression. The 3′-untranslated region of mRNAs contains regions of sequence that dictate the susceptibility of the message to nuclease cleavage and degradation. Stability appears to be sequence specific and, in some cases, dependent on transacting factors that bind to the mRNA. The mature mRNA contains elements of untranslated sequence at both the 5′ and 3′ ends that can regulate translation. Beginning in the organism’s early development, miRNAs may facilitate much more intricate ways for the regulation of gene expression, as have been shown for germline production, cell differentiation, proliferation, and organogenesis. Because recent studies have implicated the expression of miRNAs in brain development, cardiac organogenesis, colonic adenocarcinoma, and viral replication, this novel mechanism for gene silencing has potential therapeutic roles for congenital heart defects, viral disease, neurodegeneration, and cancer.

CHROMATIN REMODELING AND GENE REGULATION Both the size and complexity of the human genome with 23 chromosomes, ranging in size between 50 and 250 Mb, pose formidable challenges for transcription factors to exert the specificity of DNA-binding properties in gene regulation. Control of gene expression also takes place in diverse types of cells, often with exquisite temporal and spatial specificity throughout the life span of the organism. In eukaryotic cells, the genome is highly organized into densely packed nucleic acid DNA- and RNA-protein structures, termed chromatin.

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Section I—Introduction to Molecular Medicine

Figure 1-4 Schematic representation of a nucleosome. Rectangular blocks represent the DNA strand wrapped around the core that consists of eight histone proteins. Each histone has a protruding tail that can be modified to repress or activate transcription. (Adapted from Berg JM, Tymoczko JL, Strayer JL: Berg, Tymoczko and Stryer’s Biochemistry, 5th ed. New York, WH Freeman, 2006.)

The building blocks of chromatin are called histones, a family of small basic proteins that occupy one half of the mass of the chromosome. Histones derive their basic properties from the high content of basic amino acids, arginine, and lysine. Five major types of histones—H1, H2A, H2B, H3, and H4—have evolved to form complexes with the DNA of the genome. Two pairs each of the four types of histones form a protein core, the histone octomer, which is wrapped by 200 base pairs of DNA to form the nucleosome (Fig. 1-4). The core proteins within the nucleosomes have protruding amino-terminal ends, exposing critical lysine and arginine residues for covalent modification. Further DNA condensation is achieved as higher-order structure is imparted on the chromosomes. The nucleosomes are further compacted in layered stacks with a left-handed superhelix resulting in negative supercoils that provide the energy for DNA strand separation during replication. Condensation of DNA in chromatin precludes the access of regulatory molecules such as transcription factors. Reversal of chromatin condensation, on the other hand, typically occurs in response to environmental and other developmental signals in a tissue-dependent manner. Promoter sites undergoing active transcription, as well as relaxation of chromatin structure, that become susceptible to enzymatic cleavage by nonspecific DNAase I are called hypersensitive sites. Transcription factors on promoter sites may gain access by protein-protein interactions to enhancer elements containing tissue-specific proteins at remote sites, several thousand bases away, resulting in transcription activation or repression.

EPIGENETIC CONTROL OF GENE EXPRESSION Complex regulatory networks revolve around transcription factors, nucleosomes, chromatin structure, and epigenetic markings. Epigenetics refers to heritable changes in gene

expression without changes in the DNA sequence. Such examples include DNA methylation, gene silencing, chromatin remodeling, and X-chromosome inactivation. This form of inheritance involves the alterations in gene function without changes in DNA sequence. Chemical marking of DNA methylation is both cell specific and developmentally regulated. Methylation of the 5′ CpG dinucleotide by specific methyl transferases, which occurs in 70% of the mammalian genome, is another mechanism of gene regulation. Steric hindrance from the bulky methyl group of 5′ methylcytosine precludes occupancy by transcription factors that stimulate or attenuate gene expression. Most genes are found in CpG islands, reflecting sites of gene activity across the genome. In an analogous manner, modifications of histone by phosphorylation, methylation, ubiquination, and acetylation are transmitted and reestablished in an inheritable manner. It is conceivable that other epigenetic mechanisms do not involve genomic modifications of DNA. For example, modification of the gene encoding the estrogen receptor α has been implicated in gene silencing at 5mC sites of multiple downstream targets in breast cancer cells. Powerful new approaches are being developed to examine feedback and feed-forward loops in transmission of epigenetic markings. The concept that dynamic modifications (e.g., DNA methylation and acetylation) of histones or epigenesis contribute, in part, to tumorigenic potential for progression has already been translated into current therapies. Histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs) play antagonistic roles in the addition and removal of acetylation in the genome. Furthermore, genome-wide analysis of HATs and HDACs is beginning to provide important insights into complex modes of gene regulation. Several inhibitors of histone deacetylases, with a range of biochemical and biologic activities, are being developed and tested as anticancer agents in clinical trial. Phase I clinical trials have suggested these drugs are well tolerated. In general, the inhibition of deacetylase remodels chromatin assembly and reactivates transcription of the genome. Because the mechanisms of actions of HDACs extend to apoptosis, cell cycle control, and cellular differentiation, current clinical trials are seeking to determine the efficacy of these novel reagents in the drug compendium for human cancers.

Genetic Sequence Variation, Population Diversity, and Genetic Polymorphisms A stable, heritable change in DNA is defined as a mutation. This strict contemporary definition does not depend on the functional relevance of the sequence alteration and implicates a change in primary DNA sequence. Considered in historical context, mutations were first defined on the basis of identifiable changes in the heritable phenotype of an organism. As biochemical phenotyping became more precise in the mid-20th century, investigators demonstrated that many proteins exist in more than one form in a population, and these forms were viewed as a consequence of variations

Chapter 1—Molecular Basis of Human Disease in the gene coding for that protein (i.e., allelic variation). With advances in DNA-sequencing methods, the concept of mutation evolved from one that could be appreciated only by identifying differences in phenotype to one that could precisely be defined at the level of changes in the structure of DNA. Although most mutations are stably transmitted from parents to offspring, some are genetically lethal and thus cannot be passed on. In addition, the discovery of regions of the genome that contain sequences that repeat in tandem a highly variable number of times (tandem repeats) suggests that some mutations are less stable than others. These tandem repeats are further described later in this section. The molecular nature of mutations is varied (Table 1-1). A mutation can involve the deletion, insertion, or substitution of a single base, all of which are referred to as point mutations. Substitutions can be further classified as silent when the amino acid encoded by the mutated triplet does not change, as missense when the amino acid encoded by the mutated triplet changes, and as nonsense when the mutation leads to premature termination of translation (stop codon). On occasion, point mutations can alter the processing of precursor mRNA by producing alternate splice sites or eliminating a splice site. When a single- or double-base deletion or insertion occurs in an exon, a frameshift mutation results, usually leading to premature termination of translation at a now in-frame stop codon. The other end of the spectrum of mutations includes large deletions of an entire gene or a set of contiguous genes; deletion, duplication, and translocation of a segment of one chromosome to another; or duplication or deletion of an entire chromosome. Such chromosomal mutations play a large role in the development of many cancers. Each individual possesses two alleles for any given gene locus, one from each parent. Identical alleles define homozy-

Table 1-1 Molecular Basis of Mutations Type

Examples

Point Mutations Deletion Substitution Silent Missense Nonsense

α-Thalassemia, polycystic kidney disease Cystic fibrosis Sickle cell anemia, polycystic kidney disease, congenital long QT syndrome Cystic fibrosis, polycystic kidney disease

Large Mutations (Gene or Gene Cluster) Deletion Insertion Duplication Inversion Expanding triplet

Duchenne muscular dystrophy Factor VIII deficiency (hemophilia A) Duchenne muscular dystrophy Factor VIII deficiency Huntington disease

Very Large Mutation (Chromosomal Segment or Chromosome) Deletion Duplication Translocation

Turner syndrome (45,X) Trisomy 21 XX male [46,X; t(X;Y)]*

*Translocation onto an X chromosome of a segment of a Y chromosome that bears the locus for testicular differentiation.

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gosity and nonidentical alleles define heterozygosity for any gene locus. The heritability of these alleles follows typical mendelian rules. With a clearer understanding of the molecular basis of mutations and of allelic variation, their distribution in populations can now be analyzed precisely by following specific DNA sequences. Differences in DNA sequences studied within the context of a population are referred to as genetic polymorphisms, and these polymorphisms underlie the diversity observed within a given species and among species. Despite the high prevalence of benign polymorphisms in a population, the occurrence of harmful mutations is comparatively rare because of selective pressures that eliminate the most harmful mutations from the population (lethality) and the variability within the genomic sequence to polymorphic change. Some portions of the genome are remarkably stable and free of polymorphic variation, whereas other portions are highly polymorphic, the persistence of variation within which is a consequence of the functional benignity of the sequence change. In other words, polymorphic differences in DNA sequence between individuals can be divided into those producing no effect on phenotype, those causing benign differences in phenotype (i.e., normal genetic variation), and those producing adverse consequences in phenotype (i.e., mutations). The last group can be further subdivided into the polymorphic mutations that alone are able to produce a functionally abnormal phenotype such as monogenic disease (e.g., sickle cell anemia) and those that alone are unable to do so but in conjunction with other mutations can produce a functionally abnormal phenotype (complex disease traits [e.g., essential hypertension]). Polymorphisms are more common in noncoding regions of the genome than they are in coding regions, and one common type of these involves the tandem repetition of short DNA sequences a variable number of times. If these tandem repeats are long, they are termed variable number tandem repeats; if these repeats are short, they are termed short tandem repeats (STRs). During mitosis, the number of tandem repeats can change, and the frequency of this kind of replication error is high enough to make alternative lengths of the tandem repeats common in a population. However, the rate of change in length of the tandem repeats is low enough to make the size of the polymorphism useful as a stable genotypic trait in families. In view of these features, polymorphic tandem repeats are useful in determining the familial heritability of specific genomic loci. Polymorphic tandem repeats are sufficiently prevalent along the entire genomic sequence, enabling them to serve as genetic markers for specific genes of interest through an analysis of their linkage to those genes during crossover and recombination events. Analyses of multiple genetic polymorphisms in the human genome reveal that a remarkable variation exists among individuals at the level of the sequence of genomic DNA (genotyping). Single-nucleotide polymorphism (SNP), the most common variant, differs by a single base between chromosomes on any given stretch of DNA sequence (Fig. 1-5). From genotyping of the world’s representative population, 10 million variants (one site per 300 bases) are estimated to make up 90% of the common SNP variants in the population, with the rare variants making up the remaining 10%. With each generation of a species, the frequency of polymorphic changes in a gene is 10−4 to 10−7.

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Figure 1-5 Single nucleotide polymorphisms (SNPs), haplotypes, and tag SNPs. A stretch of mostly identical DNA on the same chromosome is shown from four different individuals. SNP refers to the variation of the three bases shown in DNA region. The combination of nearby SNPs defines a haplotype. Tag SNPs are useful tools shown (C) for genotyping four unique haplotypes from the 20 haplotypes (B). (Adapted from International HapMap Consortium: The International HapMap Project. Nature 426: 789-796, 2003.)

Thus, in view of the number of genes in the human genome, between 0.5% and 1.0% of the base sequence of the human genome is polymorphic. In this context, the new variant can be traced historically to the surrounding alleles on the chromosomal background present at the time of the mutational event. A haplotype is a specific set or combination of alleles on a chromosome or part of a chromosome (see Fig. 1-5). When parental chromosomes undergo crossover, new mosaic haplotypes, containing additional mutations, are created from such recombinations. SNP alleles within haplotypes can be co-inherited in association with other alleles in the population, termed linkage disequilibrium (LD). The association between two SNPs will decline with increasing distance, enabling patterns of LD to be decided from the proximity of nearby SNPs. Conversely, a few well-selected SNPs are often sufficient to predict the location of other common variants in the region. Haplotypes associated with a mutation are expected to become common by recombination in the general population over thousands of generations. In contrast, genetic mapping with LD departs from traditional mendelian genetics by using the entire human population as a large family tree without an established pedigree. Of the possible 10 million variants, the International HapMap Project and the Perlegen private venture have deposited more than 8 million variants comprising the public human SNP map from more than 341 people representing different population samples. The SNPs distributed across the genome of unrelated individuals provide a sufficiently robust sample set for statistical associations to be drawn between genotypes and modest phenotypes. A mutation can now be defined as a specific type of allelic polymorphism that causes a functional defect in a cell or organism.

The causal relationship between monogenic diseases with well-defined phenotypes that co-segregate with the disease requires only a small number of affected individuals compared with unaffected control individuals. In contrast, complex disorders (e.g., diabetes, hypertension, cancer) will necessitate the combinatorial effects of environmental factors and genes with subtle effects. Only through searching for variations in genetic frequency between patients and the general population can the causation of disease be discerned. In the postgenomic era, gene mapping entails the statistical association with the use of LD and high-density genetic maps that span thousands to 100,000 base pairs. To enable comprehensive association studies to become routine in clinical practice, inexpensive genotyping assays and denser maps with all common polymorphisms must be linked to all possible manifestations of the disease. Longitudinal studies of the HapMap and Perlegen cohorts will determine the effects of diet, exercise, environmental factors, and family history on future clinical events. Without similar approaches on securing adequate sample sizes and datasets, the promise of genetic population theory will not overcome the inherent limitations of linking human sequence variation with complex disease traits.

Gene Mapping and the Human Genome Project The process of gene mapping involves identifying the relative order and distance of specific loci along the genome. Maps can be of two types: genetic and physical. Genetic maps identify the genomic location of specific genetic loci by a statistical analysis based on the frequency of recombina-


A

B

C Figure 1-6 Crossing over and recombination. A, Two haploid chromosomes are shown, one from each parent (red and blue) with two genomic loci denoted by the circles and squares. B, Crossing over of one haploid chromosome from each parent. C, Resulting recombination of chromosomal segments now redistributes one haploid locus (squares) from one diploid pair to another.

tion events of the locus of interest with other known loci. Physical maps identify the genomic location of specific genetic loci by a direct measurement of the distance along the genome at which the locus of interest is located in relation to one or more defined markers. The precise location of genes on a chromosome is important for defining the likelihood that a portion of one chromosome will interchange, or cross over, with the corresponding portion of its complementary chromosome when genetic recombination occurs during meiosis (Fig. 1-6). During meiotic recombination, genetic loci or alleles that have been acquired from one parent interchange with those acquired from the other parent to produce new combinations of alleles, and the likelihood that alleles will recombine during meiosis varies as a function of their linear distance from one another in the chromosomal sequence. This recombination probability or distance is commonly quantitated in centimorgans (cM): 1 cM is defined as the chromosomal distance over which there is a 1% chance that two alleles will undergo a crossover event during meiosis. Crossover events serve as the basis for mixing parental base sequences during development and, thereby, promoting genetic diversity among offspring. Analysis of the tendency

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for specific alleles to be inherited together indicates that the recombination distance in the human genome is about 3000 cM. Identifying the gene or genes responsible for a specific polygenic disease phenotype requires an understanding of the topographic anatomy of the human genome, which is inextricably linked to interactions with the environment. The Human Genome Project, first proposed in 1985, represented an international effort to determine the complete nucleotide sequence of the human genome, including the construction of its detailed genetic, physical, and transcript maps, with identification and characterization of all genes. This foray into large-scale biology was championed by Nobel Laureate James Watson as the defining moment in his lifetime for witnessing the path from the double helix to the sequencing of 3 billion bases of the human genome, paving the way for understanding human evolution and harnessing the benefits for human health. Among the earliest achievements of the Human Genome Project were the development of 1-cM resolution maps, each containing 3000 markers, and the identification of 52,000 sequenced tagged sites. For functional analysis on a genome-wide scale, major technologic advances were made, including as high-throughput oligonucleotide synthesis, normalized and subtracted complementary DNA (cDNA) libraries, and DNA micro-arrays. In 1998, the Celera private venture proposed a similar goal as the Human Genome Project using a revolutionary approach, termed shotgun sequencing, to determine the sequence of the human genome (Web Movie 1-1). The shotgun sequencing method was designed for random large-scale sequencing and subsequent alignment of sequenced segments using computational and mathematic modeling. In the end, the Human Genome Project, in collaboration with the Celera private venture, produced a refined map of the entire human genome in 2001. Because of the differences in genomic sequence that arise as a consequence of normal biologic variations or sequence polymorphisms, the resulting restriction fragment length polymorphisms (RFLPs) differ among individuals and are inherited according to mendelian principles. These polymorphisms can serve as genetic markers for specific loci in the genome. One of the most useful types of RFLP for localization of genetic loci within the genome is that produced by tandem repeats of sequence. Tandem repeats arise through slippage or stuttering of the DNA polymerase during replication in the case of STRs; longer variations arise through unequal crossover events. STRs are distributed throughout the genome and are highly polymorphic. Of importance is that these markers have two different alleles at each locus that are derived from each parent; thus, the origins of the two chromosomes can be discerned through this analysis. The use of highly polymorphic tandem repeats that occur throughout the genome as genomic markers has provided a basis for mapping specific gene loci through establishing the association or linkage with select markers. Linkage analysis is predicated on a simple principle: the likelihood that a crossover event will occur during meiosis decreases the closer the locus of interest is to a given marker. The extent of genetic linkage can be ascertained for any group of loci, one of which may contain a disease-producing mutation (Fig. 1-7).

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A M

A M

B WT

B WT

B WT

B WT

B WT

B WT

A M

B WT

Figure 1-7 Linkage analysis. Analysis of the association (genomic contiguity) of a mutation (M) and a polymorphic allelic marker (A) shows close linkage in that the mutation segregates with the A allele, whereas the wild-type gene locus (WT) associates with the B allele.

Identifying Mutant Genes Deducing the identity of a specific gene sequence believed to cause a specific human disease requires that mutations in the gene of interest be identified. If the gene believed to be responsible for the disease phenotype is known, its sequence can be determined by conventional cloning and sequencing strategies, and the mutation can be identified. A variety of techniques are currently available for detecting mutations. Mutations that involve insertion or deletion of large segments of DNA can be detected by Southern blot, in which the isolated DNA is annealed to a radioactively labeled fragment of cDNA sequence. Prior incubation of the DNA with a specific restriction endonuclease cleaves the DNA sequence of interest at specific sites to produce smaller fragments that can be monitored by agarose gel electrophoresis. Shifts in mobility on the gel in comparison with wild-type sequence become apparent as a function of changes in the molecular size of the fragment. Alternatively, the polymerase chain reaction (PCR) can be used to identify mutations (Web Movie 1-2). In this approach, small oligonucleotides (20 to 40 bases in length), which are complementary to regions of DNA that bracket the sequence of interest and are complementary to each strand of the double-stranded DNA, are synthesized and serve as primers for the amplification of the DNA sequence of interest. These primers are added to the DNA solution. The temperature of the solution is increased to dissociate the individual DNA strands and is then reduced to permit annealing of the primers to their complementary template target sites. A thermostable DNA polymerase is included in the reaction to synthesize new DNA in the 5′-to3′ direction from the primer annealing sites. The temperature is then increased to dissociate duplex structures, after which it is reduced, enabling another cycle of DNA synthesis to occur. Several temperature cycles (usually up to 40) are used to amplify progressively the concentration of the

sequence of interest, which can be identified as a PCR product by agarose gel electrophoresis with a fluorescent dye. The product can be isolated and sequenced to identify the suggested mutation. If the gene is large and the site of the mutation is unknown (especially if it is a point mutation), other methods can be used to identify the likely mutated site in the exonic sequence. One commonly used approach involves scanning the gene sequence for mutations that alter the structural conformation of short complexes between parent DNA and PCR products, leading to a shift in mobility on a nondenaturing agarose gel (i.e., single-strand conformational polymorphism). A single-base substitution or deletion can change the conformation of the complex in comparison with wildtype complexes and yield a shift in mobility. Sequencing this comparatively small region of the gene then facilitates precise identification of the mutation. When the gene believed to cause the disease phenotype is unknown, when its likely position on the genome has not been identified, or when only limited mapping information is available, a candidate gene approach can be used to identify the mutated gene. In this strategy, potential candidate genes are identified on the basis of analogy to animal models or by analysis of known genes that map to the region of the genome for which limited information is available. The candidate gene is then analyzed for potential mutations. Regardless of the approach used, mutations identified in candidate genes should always be correlated with functional changes in the gene product because some mutations could be functionally silent, representing a polymorphism without phenotypic consequences. Functional changes in the gene product can be evaluated through the use of cell-culture systems to assess protein function by expressing the mutant protein through transiently transfecting the cells with a vector that carries the cDNA coding for the gene of interest and incorporating the mutation of interest. Alternatively, unique animal models can be developed in which the mutant gene is incorporated in the male pronucleus of oocytes taken from a super-ovulating impregnated female. This union produces an animal that overexpresses the mutant gene; that is, it produces a transgenic animal, an animal with more than the usual number of copies of a given gene, or an animal in which the gene of interest is disrupted and the gene product is not synthesized (i.e., a gene knockout animal or an animal with one half [heterozygote] or none [homozygote] of the usual number of a given gene).

MOLECULAR DIAGNOSTICS The power of molecular techniques extends beyond their use in defining the precise molecular basis of an inherited disease. By exploiting the exquisite sensitivity of PCR to amplify rare nucleic acid sequences, it is possible to diagnose rapidly a range of infectious diseases for which unique sequences are available. In particular, infections caused by fastidious or slow-growing organisms can now be rapidly diagnosed, similar to the case for Mycobacterium tuberculosis. The presence of genes conferring resistance to specific antibiotics in microorganisms can also be verified by PCR techniques. The sequencing of the entire genome of organisms such as Escherichia coli, M. tuberculosis, and Treponema pallidum now offers unparalleled opportunities to monitor

Chapter 1—Molecular Basis of Human Disease the epidemiologic structures of infections, follow the course of acquired mutations, tailor antibiotic therapies, and develop unique gene-based therapies (see later) for infectious agents for which conventional antibiotic therapies are ineffective or marginally effective. The application of molecular methods to human genetics has clearly revolutionized the field. Through the use of approaches that incorporate linkage analysis and PCR, simple point mutations can be precisely localized and characterized. At the other end of the spectrum of genetic changes that underlie disease, chromosomal translocations, deletions, or duplications can be identified by conventional cytogenetic methods. Large deletions that can incorporate many kilobase pairs and many genes can now be visualized with fluorescent in situ hybridization (FISH), a technique in which a segment of cloned DNA is labeled with a fluorescent tag and hybridized to chromosomal DNA. With the deletion of the segment of interest from the genome, the chromosomal DNA fails to fluoresce in the corresponding chromosomal location. Advances in molecular medicine have also revolutionized the approach to the diagnosis and treatment of neoplastic diseases, as well as the understanding of the mechanisms of carcinogenesis. According to current views, a neoplasm arises from the clonal proliferation of a single cell that is transformed from a regulated, quiescent state into an unregulated growth phase. DNA damage accumulates in the parental tumor cell as a result of either exogenous factors (e.g., radiation exposure) or heritable determinants. In early phases of carcinogenesis, certain genomic changes may impart intrinsic genetic instability that increases the likelihood of additional damage. One class of genes that becomes activated during carcinogenesis is oncogenes, which are primordial genes that normally exist in the mammalian genome in an inactive (proto-oncogene) state but, when activated, promote unregulated cell proliferation through activation of specific intracellular signaling pathways. Molecular methods based on the acquisition of specific tumor markers and unique DNA sequences that result from oncogenetic markers of larger chromosomal abnormalities (i.e., translocations or deletions that promote oncogenesis) are now broadly applied to the diagnosis of malignancies. These methods can be used to establish the presence of specific tumor markers and oncogenes in biopsy specimens, to monitor the presence or persistence of circulating malignant cells after completion of a course of chemotherapy, and to identify the development of genetic resistance to specific chemotherapeutic agents. In addition, through the use of conventional linkage analysis and candidate gene approaches, future studies will enable the identification of individuals with a heritable predisposition to malignant transformation. Many of these specific topics are discussed in later chapters. The advent of gene chip technologies or expression arrays has revolutionized molecular diagnostics and has begun to clarify the pathobiologic structures of complex diseases. These methods involve labeling the cDNA generated from the entire pool of mRNA isolated from a cell or tissue specimen with a radioactive or fluorescent marker and annealing this heterogeneous population of polynucleotides to a solidphase substrate to which many different polynucleotides of known sequence are attached. The signals from the

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labeled cDNA strands bound to specific locations on the array are monitored, and the relative abundance of particular sequences is compared with that from a reference specimen. Using this approach, micro-array patterns can be used as molecular fingerprints to diagnose a particular disease (i.e., type of malignancy and its susceptibility to treatment and prognosis) as well as to identify the genes whose expression increases or decreases in a specific disease state (i.e., identification of disease-modifying genes). Of course, many other applications of molecular medicine techniques are available, in addition to these applications in infectious diseases and oncology. Molecular methods can be used to sort out genetic differences in metabolism that may modulate pharmacologic responses in a population of individuals (pharmacogenomics), address specific forensic issues such as paternity or criminal culpability, and approach epidemiologic analysis on a precise genetic basis.

GENES AND HUMAN DISEASE Human genetic diseases can be divided into three broad categories: (1) those that are caused by a mutation in a single gene (e.g., monogenic disorders, mendelian traits); (2) those that are caused by mutations in more than one gene (e.g., polygenic disorders, complex disease traits); and (3) those that are chromosomal in nature (Table 1-2). In all three groups of disorders, environmental factors can contribute to the phenotypic expression of the disease by modulating gene expression or unmasking a biochemical abnormality that has no functional consequences in the absence of a stimulus or stress. Classic monogenic disorders include sickle cell anemia, familial hypercholesterolemia, and cystic fibrosis. Importantly, these genetic diseases can be exclusively produced by a single specific mutation (e.g., sickle cell anemia) or by any one of several mutations (e.g., familial hypercholesterolemia, cystic fibrosis) in a given family (Pauling paradigm). Interestingly, some of these disorders evolved to protect the host. For example, sickle cell anemia evolved as protection against falciparum malaria, and cystic fibrosis developed as protection against cholera. Examples of polygenic disorders or complex disease traits include type 1 (insulin-dependent) diabetes mellitus, atherosclerotic cardiovascular disease, and essential hypertension. A common

Table 1-2 Molecular Basis of Mutations Type Monogenic Disorders Autosomal dominant Autosomal recessive X-linked One of multiple mutations

Examples Polycystic kidney disease 1, neurofibromatosis 1 β-Thalassemia, Gaucher disease Hemophilia A, Emery-Dreifuss muscular dystrophy Familial hypercholesterolemia, cystic fibrosis

Polygenic Disorders Complex disease traits

Type 1 (insulin-dependent) diabetes, essential hypertension, atherosclerotic disease, cancer

12


example of a chromosomal disorder is the presence of an extra chromosome 21 (trisomy 21). The overall frequency of monogenic disorders is about 1%. About 60% of these include polygenic disorders, which includes those with a genetic substrate that develops later in life. About 0.5% of monogenic disorders include chromosomal abnormalities. Importantly, chromosomal abnormalities are frequent causes of spontaneous abortion and malformations. Contrary to the view held by early geneticists, few phenotypes are entirely defined by a single genetic locus. Thus, monogenic disorders are comparatively uncommon; however, they are still useful as a means to understanding some basic principles of heredity. Monogenic disorders are of three types: autosomal dominant, autosomal recessive, and X-linked. Dominance and recessiveness refer to the nature of the heritability of a genetic trait and correlate with the number of alleles affected at a given locus. If a mutation in a single allele determines the phenotype, the mutation is said to be dominant; that is, the heterozygous state conveys the clinical phenotype to the individual. In contrast, if a mutation is necessary at both alleles to determine the phenotype, the mutation is said to be recessive; that is, only the homozygous state conveys the clinical phenotype to the individual. Dominant or recessive mutations can lead to either a loss or a gain of function of the gene product. If the mutation is present on the X chromosome, it is defined as X-linked (which in males can, by definition, be viewed only as dominant); otherwise, it is autosomal. The importance of identifying a potential genetic disease as inherited by one of these three mechanisms is that, if one of these patterns of inheritance is present, the disease must involve a single genomic abnormality that leads to an abnormality in a single protein. Classically identified genetic diseases are produced by mutations that affect coding (exonic) sequences. However, mutations in intronic and other untranslated regions of the genome occur that may disturb the function or expression of specific genes. Examples of diseases with these types of mutations include myotonic dystrophy and Friedreich ataxia. An individual with a dominant monogenic disorder typically has one affected parent and a 50% chance of transmitting the mutation to his or her offspring. In addition, men and women are equally likely to be affected and equally likely to transmit the trait to their offspring. The trait cannot be transmitted to offspring by two unaffected parents. In contrast, an individual with a recessive monogenic disorder typically has parents who are clinically normal. Affected parents, each heterozygous for the mutation, have a 25% chance of transmitting the clinical phenotype to their offspring but a 50% chance of transmitting the mutation to their offspring (i.e., producing an unaffected carrier). Notwithstanding the clear heritability of common monogenic disorders (e.g., sickle cell anemia), the clinical expression of the disease in an individual with a phenotype expected to produce the disease may vary. Variability in clinical expression is defined as the range of phenotypic effects observed in individuals carrying a given mutation. Penetrance refers to a smaller subset of individuals with variable clinical expression of a mutation and is defined as the proportion of individuals with a given genotype who exhibit any clinical phenotypic features of the disorder.

Three principal determinants of variability in clinical expression or incomplete penetrance of a given genetic disorder can occur: (1) environmental factors, (2) the effects of other genetic loci, and (3) random chance. Environmental factors can modulate disease phenotype by altering gene expression in several ways, including their action on trans cription factors (e.g., transcription factors that are sensitive to cell redox state [nuclear factor κB]) or cis-elements in gene promoters (e.g., folate-dependent methylation of CpG-rich regions); or by post-translationally modifying proteins (e.g., lysine oxidation). That other genes can modify the effects of disease-causing mutations is a reflection of the overlay of genetic diversity on primary disease phenotype. Numerous examples exist of the effects of these so-called disease-modifying genes producing phenotypic variations among individuals with the identical primary disease-causing mutations (gene-gene interactions) and the effects of disease-modifying genes interacting with environmental determinants to alter phenotype further (geneenvironment interactions). These interactions are clearly important in polygenic diseases; gene-gene and geneenvironment interactions can modify the phenotypic expression of the disease. Among patients with sickle cell disease, for example, some patients experience painful crises, whereas others exhibit acute chest syndrome; still other presentations include hemolytic crises. Genetic disorders affecting a unique pool of DNA, mitochondrial DNA, have been identified. Mitochondrial DNA is unique in that it is inherited only from the mother. In addition, mutations in mitochondrial DNA can vary among mitochondria within a given cell and within a given individual (heteroplasmy). Examples of genetic disorders based in the mitochondrial genome are Kearns-Sayre syndrome and Leber hereditary optic neuropathy. The list of known mitochondrial genomic disorders is growing rapidly, and mitochondrial contributions to a large number of common polygenic disorders may also exist.

MOLECULAR MEDICINE A principal goal of current molecular strategies is to restore normal gene function to individuals with genetic mutations. Methods to do so are currently primitive, and a number of obstacles must be surmounted for this approach to be successful. The principal problems are that to deliver a complete gene into a cell is not easy, and persistent expression of the new gene cannot be ensured because of the variability in its incorporation in the genome and the consequent variability in its regulated expression. Many approaches have been used to date, but none has been completely successful. They include the following: (1) packaging the cDNA in a viral vector, such as an attenuated adenovirus, and using the cell’s ability to take up the virus as a means for the cDNA to gain access to the cell; (2) delivering the cDNA by means of a calcium phosphate–induced perturbation of the cell membrane; and (3) encapsulating the cDNA in a liposome that can fuse with the cell membrane and thereby deliver the cDNA. After the cDNA has been successfully delivered to the cell of interest, the magnitude and durability of expression of the gene product are important variables. The magnitude of expression is determined by the number of copies of cDNA

Chapter 1—Molecular Basis of Human Disease taken up by a cell and the extent of their incorporation in the genome of the cell. The durability of expression appears to be dependent partly on the antigenicity of the sequence and protein product. Notwithstanding these technical limitations, gene therapy has been used to treat adenosine deaminase deficiency successfully, which suggests that the principle on which the treatment is based is reasonable. Clinical trials of gene therapy have slowed considerably after unexpected deaths were widely reported in both the scientific and lay media. Efforts on other genetic disorders and as a means to induce expression of a therapeutic protein (e.g., vascular endothelial cell growth factor to promote angiogenesis in ischemic tissue) are ongoing. Understanding the molecular basis of disease leads naturally to the identification of unique disease targets. Recent examples of this principle have led to the development of novel therapies for diseases that have been difficult to treat. Imatinib, a tyrosine kinase inhibitor that is particularly effective at blocking the action of the bcr-abl kinase, is effective for the treatment of chronic-phase chronic myelogenous leukemia. Monoclonal antibody to tumor necrosis factor-α (infliximab) and soluble tumor necrosis factor-α receptor (etanercept) are prime examples of biologic modifiers that are effective in the therapy of chronic inflammatory disorders, including inflammatory bowel disease and rheumatoid arthritis. This approach to molecular therapeutics is rapidly expanding and holds great promise for improving the therapeutic armamentarium for a variety of diseases. Beyond cancer-related categories (e.g., DNA, RNA repair), gene expression arrays have provided additional interactions of regulatory pathways of clinical interest. The limitation of gene expression profile using micro-arrays, which does not account for post-transcriptional and other post-translational modifications of protein-coding products, will likely be overcome by approaches and advances in proteomics. Such processes by signaling networks tend to amplify or attenuate gene expression on time scales lasting seconds to weeks. Much work remains to improve current knowledge about the pathways that initiate and promote tumors. The basic pathways and nodal points of regulation will be identified for rational drug design and target from mechanistic insights gleaned from expression profiling of cultured cell lines, from small animal models of human disease, and from human samples. Although accounting for tissue heterogeneity and variation among different cell types, the new systems’ approach for incorporating genomic and computational research appears particularly promising to decipher the pathways that promote tumorigenesis. In turn, biologists and clinicians will use information derived from these tools to understand the events that promote survival, proangiogenesis, and immune escape, all of which may confer metastatic potential and progression. What potential diagnostic tools are available to establish genetic determinants of drug response? Genome-wide approaches from the Human Genome Project in combination with micro-arrays, proteomic analysis, and bioinformatics will identify multiple genes encoding drug targets (e.g., receptors). Similar high-throughput screening should provide insights into the predisposition to adverse effects of outcomes from treatments that are linked to genetic polymorphisms.

13

PHARMOCOGENETICS The future of pharmacogenetics is to know all the factors that influence adverse drug effects. In this way, the premature abandonment of special drug classes can be avoided in favor of rational drug design and therapy. Many hurdles must be overcome for pharmacogenetics to become more widespread and to be integrated into medical practice. Current approaches of trial and error in medical practice are well engrained on the parts of physicians. In addition, the allure for blockbuster drugs by the pharmaceutical industry warrants a new model for approaching individualized doses. New training for physicians in molecular biology and genetics should complement clinical pharmacogenomic studies that determine efficacy in an era of evidence-based medicine. Pharmacogenetic polymorphisms, unlike other clinical variables such as renal function, need only a single test, ideally as a newborn. Polygenic models of therapeutic optimization still face hurdles that reduce the chances for abuse of genetic information and additional costs. On the other hand, SNP haplotyping has the potential to identify genetically similar subgroups of the population and to randomize therapies based on more robust genetic markers. On a population level, genomic variability is much greater within than among distinct racial and ethnic groups. Both therapeutic efficacy and host toxicity are influenced by the patient’s specific disease, age, renal function, nutritional status, and other co-morbid factors. New challenges will be posed for the selection and guide to drug therapy for patients with cancer, hypertension, and diabetes. It is conceivable that treatment of multisystem disorders (e.g., metabolic syndrome) might be derived from novel therapeutics based on individual, interacting, and complementary molecular pathways.

REGENERATIVE MEDICINE A new era of regenerative biology has emerged with the discovery that adult mammalian cells can be reprogrammed into new cells. Regenerative medicine entails novel applications and approaches to exploit the resident population of progenitor cells for regeneration or repair of damaged tissues. After irreversible damage, transplantation of solid organs such as the heart, kidney, and lungs is a wellestablished medical-surgical intervention, but the limited availability of organs restricts widespread applications. Manipulation of cultured cells for transplantation heralds an alternative and complementary strategy to solid organ transplantation and offers an expanded platform for regenerative medicine. Although postmitotic, terminally differentiated organs are devoid of significant regenerative capacity, recent evidence for cellular plasticity of adult solid organs, throughout adult life, has challenged this prevailing dogma. This makeover involves approaches either to convert adult into pluripotent stem cells—retaining the ability to differentiate into new cell types—or forced reprogramming of adult cells into mature or progenitor cells. Embryonic stem (ES) cells share common features of clonagenicity, self-renewal, and multi-potentiality, a prerequisite for differentiation into diverse cell lineages of multicellular adult organism. Both technical and ethical concerns propelled the search for new sources, including

14


the isolation of ES cells from a single blastomere, which circumvents destruction of the embryo, and the use of postimplantation embryos as ES cell donors. Somatic cell nuclear transplantation (SCNT) or nuclear transfer (NT) is a technique for successful cloning and reprogramming of adult animal cell nuclei from healthy oocyte host cells. SCNT provides a source of stem cells tailored to the donor organism and promises to accelerate the pace for human use. Induced pluripotent stem (iPS) cells share the common features of somatic cell reprogramming but with the aid of four transcription factors by retroviral transduction. Whether symmetrical and asymmetrical cell division promotes the differentiation of pluripotent progenitor cells into distinct lineages of the mature organ awaits future studies. It is conceivable that age, gender, risk factors, and other disease status will have an impact on regenerative

plasticity, proliferation, or cellular functions. Another future hurdle will be to determine whether genetic factors enhance the cellular and molecular properties of ES cells essential for the reconstitution of a well-differentiated organ in vivo. Might progenitor cells derived from bone marrow or circulating blood be administered safely and efficaciously? Both clinical and translational scientists are being asked to address whether stem cell therapy has efficacy for the current victims of either stroke or heart attack. Beyond the feasibility are questions related to benefits from transplantation of different cells originating from embryonic, fetal, or adult stem cell lineages. Whether priming of endogenous cell-mediated repair mechanisms using genetically engineered cell lines leads to improvement in selected endpoints and clinical outcomes awaits large-scale clinical trials.

Prospectus for the Future The concept of personalized medicine will be realized from the functional and analytical phenotyping that aids diagnosis and treatment based on the individual’s genome and disease profile. An important future challenge will be the extraction of biologically meaningful data of direct clinical relevance to diagnosis, prognosis, therapeutic response, and, ultimately, prevention. What are the functional consequences of genome occupancy and modification in health and disease? Computational analyses will play an increasing role in understanding cancer pathogenesis and the mechanisms of disease. Information about the hierarchy of cellular functions is being coupled with powerful approaches to derive different yet complementary perspectives about molecular mechanisms. Micro-array analysis has already

References Acharya MR, Sparreboom A, Venitz J, Figg WD: Rational development of histone deacetylase inhibitors as anticancer agents: A review. Mol Pharmacol 68:917-932, 2005. Collins FS, Green ED, Guttmacher AE: A vision for the future of genomics research. Nature 422:835-847, 2003. Evans WE, McLeod HL: Pharmacogenomics: Drug disposition, drug targets, and side effects. N Engl J Med 348:538-549, 2003.

provided new classes of hematologic diseases and prognostic factors in breast cancer. Experimental approaches are already underway to reduce tumorigenesis into discrete modules of regulatory networks and biologic processes. A catalog of listed genes that change with tumor type, for example, should not be equated with prognosis, therapeutic response, or adverse outcomes. How to move diagnostic tools using micro-arrays and gene expression profiles into clinical decision making will be the focus of research programs in translational and clinical outcomes. Specific therapies for many inheritable diseases have lagged substantially behind advances in other fields, but new opportunities appear on the horizon for improving prognosis and clinical outcomes in the era of regenerative medicine.

Hinds DA, Stuve LL, Nilsen GB, et al: Whole-genome patterns of common DNA variation in three human populations. Science 307:1072-1079, 2005. Krause DS, Van Etten RA: Tyrosine kinases as targets for cancer therapy. N Engl J Med 353:172-187, 2005. van Steensel B: Mapping of genetic and epigenetic regulatory networks using microarrays. Nat Genet 37:S18-S24, 2005. Willard HF, Ginsburg GS (eds): Genomic and Personalized Medicine. New York, Elsevier, 2009. Zamore PD, Haley B: Ribo-gnome: The big world of small RNAs. Science 309:1519-1524, 2005.

Section II Evidence-Based Medicine

2

Evidence-Based Medicine, Quality of Life, and the Cost of Medicine – TARIQ * BELAND

II

Chapter

2

Evidence-Based Medicine, Quality of Life, and the Cost of Medicine Sara G. Tariq and Susan S. Beland

T

he diagnosis and treatment of individual patients involve clinical experience and skills on the part of the physician and knowledge of scientific information obtained through clinical trials. In the past, most of the daily practice was based on informal learning and a tradition of knowledge transferred from experienced clinicians to trainees and colleagues. Increasingly, however, this informal technique is being supplanted by rigorous analysis of the scientific underpinnings of clinical logic. Electronic databases and Internet technology enable collation and dissemination of information to help identify which techniques are supported by clinical trials. Evidence-based medicine has evolved during the past decade and uses the best available evidence from published research as the foundation for clinical decision making. This foundation, in addition to clinical expertise and a respect for patient preference, will aid the physician in providing optimal outcomes and a quality of life for the patient. However, the development of new techniques in medicine, often at great cost, can strain the ability of a society to fund and provide such services. Critical appraisal of both new and traditional diagnostic and treatment modalities is thus needed.

Critical Appraisal of the Literature Being cognizant of the types of evidence is crucial to practice evidence-based medicine. Research studies can be divided into two major categories: primary and secondary (Table 2-1). Primary studies can have a number of designs. In ran domized controlled studies, participants in the trial are ran16

domly allocated to one intervention or another. Both groups are followed for a specified period and analyzed in terms of specific outcomes defined at the outset of the study. This type of study allows rigorous assessment of a single variable in a defined patient group, has a prospective design that potentially eradicates bias by comparing two otherwise similar groups, and allows for meta-analysis. However, these studies are expensive and time-consuming. Results of randomized controlled trials can have enormous impact on the practice of medicine, as exemplified by the Women’s Health Initiative randomized controlled trial. This study was designed to assess the risks and benefits for postmenopausal hormone use in healthy women. However, the trial was stopped early because of an increased incidence of breast cancer, coronary heart disease, stroke, and thromboembolic disease in the hormone-treated group. Cohort studies have two or more groups of participants selected on the basis of differences in their exposure to a particular agent. The participants are prospectively followed to see how many in each group develop a disease or other specific outcome. A well-known example is the Framingham Heart Study that enrolled 5200 participants in 1948 and followed them forward in time to examine the progression and risk factors for heart disease. The data provided from the Framingham Study have helped clinicians understand the development and progression of heart disease and its risk factors. As with randomized trials, cohort studies are time-consuming. Case-control studies involve patients with a particular disease or condition who are identified and matched with control patients. The control participants can be patients with another disease or individuals from the general population. The validity of these retrospective studies depends on careful selection of the control group. For example, the impact of risk factors for men and women was recently evaluated in the CARDIO 2000 Study. The authors

Chapter 2—Evidence-Based Medicine, Quality of Life, and the Cost of Medicine Table 2-1 Types of Research Studies

Table 2-2 Requirements of Screening Tests

Primary Studies

Secondary Studies

Randomized control Case control Cohort studies Cross sectional Case series Case report

Meta-analyses Clinical practice guidelines Decision analysis Cost-effectiveness analysis

• Prevalence of disease must be sufficiently high. • Disease must have significant morbidity and mortality rates. • Effective treatment must be available. • Improved outcomes from early diagnosis and treatment must be present. • Test should have good sensitivity and specificity parameters. • Test should carry acceptable risks and be cost-effective.

evaluated 848 hospitalized patients after their first episode of acute coronary syndrome and used 1078 age- and sexmatched controls. The data revealed that women experiencing their first event were significantly older than men. Case reports describe the medical history of a single patient. When medical histories of more than one patient with a particular condition are described together to illustrate one aspect of the disease process, the term case series is used. Secondary (integrative) studies attempt to summarize and draw conclusions from primary information. Meta-analyses use statistical techniques to combine and summarize the results of primary studies. By combining the results from many trials, meta-analyses are able to estimate the magnitude of the effect of an intervention or risk factor as well as evaluate previously unanswered questions by performing subgroup analyses. The use of meta-analysis has provoked some controversy. Some investigators believe that metaanalyses may be as reliable as randomized controlled trials, whereas others believe that the technique should be used only as an alternate to randomized trials. However, in the absence of a large randomized controlled study, a metaanalysis of multiple smaller studies may be the best source of information to answer a specific question. Clinical practice guidelines attempt to summarize diagnostic and treatment strategies for common clinical problems to assist the physician with specific circumstances. They are usually published by medical organizations, such as the American College of Physicians, and government agencies, such as the Agency for Health Care Policy and Research and the United States Preventive Services Task Force. Decision analysis uses the results of primary studies to generate probability trees to aid both health professionals and patients in making choices about clinical management. Cost-effectiveness analysis evaluates whether a particular course of action is an effective use of resources.

Testing in Medical Practice Screening tests are performed on asymptomatic healthy people to detect occult disease and should meet the criteria listed in Table 2-2. Screening tests are most useful when a high prevalence of disease is present in the population and the test has adequate sensitivity and specificity parameters. When applied to a disease with low prevalence, a test with low specificity would have an unacceptable number of falsepositive results, which would lead to further procedures that are often invasive and expensive.

17

Diagnostic tests are used to determine the cause of illness in symptomatic persons and can be helpful in patient management by evaluating the severity of disease, determining prognosis, detecting disease recurrence, or selecting appropriate medications or other therapies. When considering diagnostic tests, the physician should weigh the potential benefits against the risks and expense. When comparing the efficacy of a new diagnostic test, the critical issues are the following: (1) Does the new test have something to offer that the currently accepted test does not? (2) Does the new test provide additional information that alters the post-test probability, which is the likelihood that a patient who has a positive test has the disease? Comparing the post-test probability with the pre-test probability before ordering the test, which is the clinical assessment of diagnostic possibilities, is also important. Values for some pre-test probabilities have been published, but more often they are derived from the physician’s clinical experience and are influenced by the practice setting. For instance, an obese African-American woman from the rural South is experiencing fatigue, blurry vision, and frequent vaginal yeast infections, and she has a strong family history of diabetes. Based on these features, she would have a high pre-test probability for type 2 diabetes mellitus. If a new diagnostic test were available for the diagnosis of diabetes, a comparison could be made on the post-test probabilities expected from the standard test (fasting blood glucose) and the new test. Ideally, the new test would offer greater diagnostic accuracy. Sensitivity and specificity are important parameters to consider when evaluating a diagnostic test. Sensitivity is an index of the diagnostic test’s ability to detect the disease when it is present. Specificity is the ability of the diagnostic test to identify correctly the absence of the disease. These parameters are calculated by the use of a 2 × 2 table (Table 2-3). An additional value, the likelihood ratio, which uses

Table 2-3 Schematic Outcomes of a Diagnostic Test (2 × 2 Table) Test Result

Disease Present

Disease Absent

Positive Negative

True positive (a) False negative (c)

False positive (b) True negative (d)

Positive predictive value (true-positive rate) =a/(a+b). Negative predictive value (false-positive rate) =d/(c+d). Sensitivity =a/(a+c); patients with the disease who have a positive test. Specificity =d/(b+d); patients without the disease who have a negative test.

18

Section II—Evidence-Based Medicine

both sensitivity and specificity, gives an even better indication of the test’s performance. A high positive likelihood ratio indicates a high likelihood of the presence of disease, whereas a high negative likelihood ratio identifies the absence of disease. Positive likelihood ratio: Sensitivity ( probability that test is positive in diseased patients ) = 1 − Specificity ( probability that test is positive in nondiseased patients)

Negative likelihood ratio: 1 − Sensitivity ( probability that test is negative in diseased d patients ) = 1 − Specificity ( probability that test is negative in nondiseased patients) After determining the validity of the diagnostic test, its applicability to the patient in question and whether the test is affordable and accurate in a particular setting should be ascertained. If the diagnostic test requires special devices or skills that are not available in the practice facility, the results provided can be inaccurate. Most importantly, an assessment should be made about whether the test will change the management offered or decrease the need for the use of other tests.

Evaluating Evidence about Treatment One of the most common problems facing physicians is the need to assess the validity of new treatments being developed as well as validity of traditional treatments that have been used for years. For example, how long after discharge from the hospital should treatment with antimicrobial agents continue for the patient who had been hospitalized for pneumonia? What is the value of plasmapheresis in thrombotic thrombocytopenic purpura? The first step in evaluating prospective treatments is to assess whether the information is derived from a properly conducted randomized controlled study. Every patient who enters the trial must be accounted for at the end of the study. The patients who are lost to follow-up often have different outcomes. If the conclusion of the trial does not change after accounting for the lost patients, then validity is added to the study. Another point to consider is whether patients were analyzed in their original randomized groups even if they did not undergo the intervention in question. This is termed an intention-to-treat analysis. A description of whether both groups were treated differently regarding other interventions (e.g., co-interventions) should be included. Assessing the importance of the data provided is the next step. This includes a number of simple statistical calculations

applied to the available results. The first is relative risk reduction (RRR): Incidence of outcome in control group − Incidence of outcome in study group RRR = Incidence of outcome in control group For example, the Diabetes Control and Complications Trial investigated the effect of tight control of blood glucose in patients with type 1 diabetes on the development and progression of long-term complications. The study involved more than 1400 patients, with one half randomized to intensive treatment and one half to conventional therapy. In this study, 3.4% of the patients in the conventional group and 2.2% in the intensive group developed microalbuminuria, indicating a 35% decrease in the occurrence of microalbuminuria in the primary prevention group: RRR =

0.034 − 0.022 × 100 = 35% 0.034

The greater the RRR, the more effective the therapy. However, the RRR does not take into account the baseline risk of the patients entering the trial and thus does not differentiate between large and small effects. The significance of RRR is discussed on the web site (Web Text 2-1). Calculating the absolute risk reduction (ARR), which gives the absolute difference in rates between the two groups, is another way of assessing the outcome. The ARR is defined as the number (X) that had the ill effect in the control group minus the number (Y) in the treatment group (i.e., ARR = X − Y). Using the previous example, the ARR for the development of microalbuminuria is 0.034 − 0.022 = 0.012, or 1.2%. Another valuable calculation is the number needed to treat, which represents the number of patients who need to be treated to prevent a single outcome event and is the inverse of the ARR (i.e., 1/[X − Y]). The lower the number needed to treat, the more clinically relevant is the treatment. Again, using the example, to prevent 1 patient from developing microalbuminuria, 83 patients with diabetes would have to be treated with intensive therapy (1/[X − Y] = 1/0.012 = 83). From this example, what seems like a large RRR of 35% actually translates to a relatively small (although significant) number of patients who benefited from intensive treatment. As before, assessment of the applicability of this information to a particular patient should be made by taking into account whether the patient in question has the same characteristics of the patients included in the study. Evidence of side effects, cause, or value of a particular clinical sign in diagnosis can be assessed along these same lines.

Internet in Clinical Practice The use of computer systems for disseminating medical information has increased exponentially. Numerous worldwide websites offer high-quality medical news, information

Chapter 2—Evidence-Based Medicine, Quality of Life, and the Cost of Medicine Table 2-4 Worldwide Websites • Cochrane Collaboration—one of the major organizations involved in evidence-based medicine (http://www.cochrane. org) • MD Consult—comprehensive medical information service (http://www.mdconsult.com) • Centers for Disease Control and Prevention (http://www .cdc.gov) • National Institutes of Health (http://www.nih.gov) • UpToDate—comprehensive clinical information website that is constantly updated (http://www.uptodate.com) • Student Consult—provides access to full standard texts online (http://www.studentconsult.com)

about practice guidelines, online textbooks and journals, and information about evidence-based medicine. In addition, many government sites offer up-to-date information (e.g., Centers for Disease Control and Prevention, National Institutes of Health). Table 2-4 lists some of these sites.

Including the Patient in the Decision Process Searching for the best evidence and applying it have the ultimate goal of providing better patient care. The process should also involve informing the patient of the available options and offering options based on good evidence. Effective communication, geared toward the patient’s level of health literacy, is crucial to ensure that the patient makes an informed decision. Using a certain therapy or implementing a diagnostic test may be inconvenient, or the patient may develop a certain side effect that he or she is not willing to accept. Involvement of the patient in the decisionmaking process requires good communication and adequate resources for patient education.

Quality of Life Health care in the millennium has changed significantly. An increasing number of patients survive illnesses that used to be fatal, and many patients have multiple co-existing illnesses. Assessing clinical improvement to a given treatment covers only one aspect of the clinician’s success. For example, although survival is an important outcome for patients with cancer, overall quality of life is fundamental. A patient can have improvement in disease-free survival without having a significant change in quality of life, and vice versa. Quality of life represents a subjective concept that is defined by the subjective perception of the patient and includes physical, emotional, social, and cognitive functions and the disease symptoms and side effects of a given treatment or intervention. For example, in examining the efficacy of a drug for postchemotherapy anemia, it would not only be important to know whether the hemoglobin rises appropriately but also to know whether the patient subjectively has more energy and is able to perform the normal duties of life. Quality of life is more commonly becoming a defined outcome measure in clinical trials. An increasing number of studies have been conducted in which health-related quality

19

of life is either the primary or secondary endpoint. Hopefully, clinicians can then take the information gained from these data and apply it in a holistic manner to optimize patient care.

COST OF MEDICINE The practice of medicine has significantly changed during the past 30 years. The cost of medicine has risen astronomically, and it is the duty of the physician to be cognizant of this in daily practice. Health care spending is growing much faster than the rest of the economy. Rising hospital expenses reflect many factors, including the demand for new medications and technology as well as the aging population. Physicians can contribute to the reduction of costs by being aware of medication prices and ordering tests appropriately. The pharmaceutical industry has been accused of contributing to medical inflation. The industry spends more than $11 billion annually on promotion and marketing, and $8,000 to $13,000 per physician each year. They employ 1 drug representative for every 11 physicians in the United States. The average price of drugs rose almost 50% between 1992 and 2000. Literature suggests that the gifts and perks physicians receive from the pharmaceutical representatives have a major influence on their practices and prescribing habits. Caution is recommended when analyzing data from pharmaceutical representatives, taking into account the inherent bias that exists regarding the medication they are marketing. The medical profession is responsible for providing the best care possible for patients, and barriers to this care arise when a gift or amenity accepted from a pharmaceutical representative obscures the judgment of appropriate and cost-effective care. Generic drugs should be prescribed whenever possible. Studies have shown that if physicians substituted generic drugs for brand-name drugs, the potential national savings would be up to 5.9 billion dollars annually. In addition, all medical schools should stress the use of generic drugs to students and residents. The use of tests is the second area in which physicians must be prudent when it comes to cost. The routine ordering of expensive and unnecessary tests has become part of the medical culture, but they can never take the place of a thorough history and physical examination. Evidence-based medicine is an important tool to use when deciding whether a certain diagnostic test is needed to help in the care of a patient. The risks and benefits of each test that is ordered must be weighed against the costs. For example, asymptomatic patients who are concerned about ovarian cancer may want their physician to order a pelvic ultrasound. The prudent physician will know that the prevalence of ovarian cancer is low in the population and thus the literature does not support the routine use of pelvic ultrasound as a screening tool. Therefore, a pelvic ultrasound is not a costeffective test for screening ovarian cancer in all female patients. These are two ways in which physicians can take an active role in helping reduce the cost of medical care in this nation, but the problem is clearly larger than this. Physicians will need to find a balance between being cost-conscious and maintaining high-quality patient care as the medical field continues to expand.

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Section II—Evidence-Based Medicine

Prospectus for the Future Challenges to be met: • Medical schools need to expand the teaching of evidencebased medicine to students and physicians in training. • Risks and benefits of screening tests need to be better defined (e.g., use of computed tomography in the diagnosis of early lung cancer versus risk for radiation exposure).

References Bhat SK: The cost of medicine. Ann Intern Med 139:74-75, 2003. Bottomley A: The cancer patient and quality of life. Oncologist 7:120-125, 2002. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-986, 1993. Haas JS, Phillips KA, Gerstenberger EP: Potential savings from substituting generic drugs for brand-name drugs: Medical expenditure panel survey, 1997-2000. Ann Intern Med 142:891-897, 2005.

• To affect the cost of medicine, the overuse of technology (e.g., computed tomography for every patient with abdominal pain) needs to be addressed from the standpoint of evidence-based medicine. • Finally, universal health care coverage for all people in the United States is desperately needed.

Hall WJ: The ethical dilemma of accepting gifts from drug makers. ACP-ASIM Observer, December, 2001. Sacket D: Evidence-Based Medicine, 2nd ed. Oxford, Churchill Livingstone, 2000, pp 13-29. Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women, JAMA 288:321333, 2002.

Section III Cardiovascular Disease

3

Structure and Function of the Normal Heart and Blood Vessels – MORSHEDZADEH * LI * BENJAMIN

4

Evaluation of the Patient with Cardiovascular Disease – LITWIN * BENJAMIN

5

Diagnostic Tests and Procedures in the Patient with Cardiovascular Disease – LITWIN

6

Heart Failure and Cardiomyopathy – LITWIN * BENJAMIN

7

Congenital Heart Disease –

8

Acquired Valvular Heart Disease –

9

Coronary Heart Disease –

10

Cardiac Arrhythmias –

11

Pericardial and Myocardial Disease –

WHITEHEAD LITWIN

MICHAELS

HAMDAN

STEHLIK * BENJAMIN

12

Other Cardiac Topics –

13

Vascular Diseases and Hypertension – VONGPATANASIN * VICTOR

BULL * BENJAMIN

III

Chapter

3

Structure and Function of the Normal Heart and Blood Vessels Jack Morshedzadeh, Dean Y. Li, and Ivor J. Benjamin

Gross Anatomy The heart is composed of four chambers, two atria and two ventricles, which form two separate pumps arranged side by side and in series (Fig. 3-1). The atria are low-pressure capacitance chambers that mainly function to store blood during ventricular contraction (systole) and then fill the ventricles with blood during ventricular relaxation (diastole). The two atria are separated by a thin interatrial septum. The ventricles are high-pressure chambers responsible for pumping blood through the lungs and to the peripheral tissues. Because the pressure generated by the left ventricle is greater than that generated by the right, the left ventricular myocardium is thicker than the right. The two ventricles are separated by the interventricular septum, which is a membranous structure at its superior aspect and a thick, muscular structure at its medial and distal portions. The atrioventricular (AV) valves separate the atria and ventricles. The mitral valve is a bileaflet valve that separates the left atrium and ventricle. The tricuspid valve is a trileaflet valve and separates the right atrium and ventricle. Strong chords (chordae tendineae) attach the ventricular aspects of these valves to the papillary muscles of their respective ventricles. These papillary muscles are extensions of normal myocardium that project into the ventricular cavities and are important for optimal valve closure. The semilunar valves separate the ventricles from the arterial chambers: the aortic valve separates the left ventricle from the aorta, and the pulmonic valve separates the right ventricle from the pulmonary artery. These valves do not have chordae. Rather, they are fibrous valves whose edges coapt closely, thus allowing for adequate valve closure. Each of the four valves is surrounded by a fibrous ring, or annulus, that forms part of the structural support of the heart. When open, the valves 22

allow free flow of blood across them and into the adjacent chamber or vessel. When closed, the valves effectively prevent the backflow of blood into the preceding chamber. The thin, double-layered pericardium surrounds the heart. The visceral pericardium is adherent to the heart and constitutes its outer surface, or epicardium. This outer surface is separated from the parietal pericardium by the pericardial space, which normally contains less than 50 mL of fluid. The parietal pericardium has attachments to the sternum, vertebral column, and diaphragm that serve to stabilize the heart in the chest. Normal pericardial fluid lubricates contact surfaces and limits direct tissue-surface contact during myocardial contraction. In addition, the normal pericardium modulates interventricular interactions during the cardiac cycle.

Circulatory Pathway The circulatory system is composed of two distinct and parallel vascular networks, arterial and venous networks, which interconnect through capillary beds of the distal target organs (see Fig. 3-1). Deoxygenated blood drains from peripheral tissues and enters the right atrium through the superior and inferior venae cavae. Blood draining from the heart enters the right atrium through the coronary sinus. This blood mixes in the right atrium during ventricular systole and then flows across the tricuspid valve and into the right ventricle during ventricular diastole. When the right ventricle contracts, blood is ejected across the pulmonic valve and into the main pulmonary artery, which then bifurcates into the left and right pulmonary arteries as these branches enter their respective lungs. After multiple bifurcations, blood flows into the pulmonary capillaries, where

Chapter 3—Structure and Function of the Normal Heart and Blood Vessels Head, upper extremities Superior vena cava Pulmonary artery

Pulmonary circulation

Bronchial arteries

Coronary circulation Ostium of coronary sinus

Aorta Left atrium

Right atrium Right ventricle Inferior vena cava

Left ventricle Abdominal viscera

“Capacitance” function of the venous system Venous valves

Lower extremities

“Resistance” function of the arterial system Figure 3-1 Schematic representation of the systemic and pulmonary circulatory systems. The venous system contains the greatest amount of blood at any one time and is highly distensible, accommodating a wide range of blood volumes (high capacitance). The arterial system is composed of the aorta, arteries, and arterioles. Arterioles are small muscular arteries that regulate blood pressure by changing tone (resistance).

Superior vena cava

23

carbon dioxide is exchanged for oxygen across the alveolarcapillary membrane. Oxygenated blood then drains from the lungs into the four pulmonary veins, which empty into the left atrium. During ventricular diastole, the blood flows across the open mitral valve and into the left ventricle. With ventricular contraction, the blood is ejected across the aortic valve and into the aorta and is subsequently delivered to the various organs, where oxygen and nutrients are exchanged for carbon dioxide and metabolic wastes. The heart receives blood through the left and right coronary arteries (Fig. 3-2). These are the first arterial branches of the aorta and originate in outpouchings of the aortic root called the sinuses of Valsalva. The left main coronary artery originates in the left sinus of Valsalva and is a short vessel that bifurcates into the left anterior descending (LAD) and the left circumflex (LCx) coronary arteries. The LAD travels across the surface of the heart in the anterior interventricular groove toward the cardiac apex. It supplies blood to the anterior and anterolateral left ventricle through its diagonal branches and to the anterior two thirds of the interventricular septum through its septal branches. The LCx traverses posteriorly in the left AV groove (between the left atrium and left ventricle), supplying blood to the lateral aspect of the left ventricle through obtuse marginal branches as well as giving off branches to the left atrium. The right coronary artery (RCA) originates in the right sinus of Valsalva and courses down the right AV groove to a point where the left and right AV grooves and the inferior interventricular groove meet, the crux of the heart. The RCA gives off atrial branches to the right atrium and acute marginal branches to the right ventricle. The blood supply to the diaphragmatic and posterior aspects of the left ventricle varies. In 85% of individuals, the RCA bifurcates at the crux into the posterior descending coronary artery (PDA), which travels in the inferior interventricular groove to supply blood to the inferior

Aortic arch

Superior vena cava

Pulmonary artery Left atrium

Left main coronary artery Left circumflex coronary artery Left anterior descending coronary artery (LAD) Diagonal branch of LAD Right ventricle Left ventricle Right coronary artery

Right coronary artery Figure 3-2 Major coronary arteries and their branches.

24

Section III—Cardiovascular Disease

left ventricular wall and inferior third of the interventricular septum and to the posterior left ventricular (PLV) branches, which supply the posterior left ventricle. This course is termed a right dominant circulation. In 10% of individuals, the RCA terminates before reaching the crux, and the LCx supplies the PLV and PDA. This course is termed a left dominant circulation. In the remaining individuals, the RCA gives rise to the PDA, and the LCx gives rise to the PLV in a co-dominant circulation. An understanding of coronary artery anatomy and distribution of blood supply enables the clinician to define the location of coronary artery disease based on history, physical examination, and noninvasive tests such as electrocardiography (ECG), echocardiography, and radionuclide ventriculography. Small vascular channels, called collateral vessels, interconnect the normal coronary arteries. These vessels are nonfunctional in the normal myocardium because no pressure gradient develops across them. However, in the setting of severe stenosis or complete occlusion of a coronary artery, the pressure in the vessel distal to the stenosis decreases, and a gradient develops across the collateral vasculature, resulting in flow through the collateral vessel. The development of collateral vasculature is directly related to the severity of the coronary stenosis and may be stimulated by ischemia, hypoxia, and a variety of growth factors. Over time, these vessels may reach up to 1 mm in luminal diameter and are almost indistinguishable from similarly sized, normal coronary arteries. Most of the venous drainage from the heart occurs through the coronary sinus, which runs in the AV groove and empties into the right atrium. A small amount of blood from the right side of the heart drains directly into the right atrium through the thebesian veins and small anterior myocardial veins.

Conduction System The electrical impulse that initiates cardiac contraction originates in the sinoatrial (SA) node, a collection of specialized pacemaker cells measuring 1 to 2 cm in length located high in the right atrium between the superior vena cava and the right atrial appendage (Fig. 3-3). The impulse then spreads through the atrial tissue and through preferential internodal tracts, ultimately reaching the AV node. This structure consists of a meshwork of cells located at the inferior aspect of the right atrium between the coronary sinus and the septal leaflet of the tricuspid valve. The AV node provides the only normal electrical connection between the atria and ventricles. After an electrical impulse enters the AV node, conduction transiently slows and then proceeds to the ventricles by means of the HisPurkinje system. The bundle of His extends from the AV node down the membranous interventricular septum to the muscular septum, where it divides into the left and right bundle branches. The right bundle branch is a discrete structure that extends along the interventricular septum and enters the moderator band on its way toward the anterolateral papillary muscle of the right ventricle. The left bundle branch is less distinct; it consists of an array of fibers organized into an anterior fascicle, which proceeds toward the anterolateral papillary muscle of the left ventricle, and a posterior fascicle, which proceeds posteriorly in the septum

Aorta Sinoatrial node

Bundle of His Main left bundle branch Atrioventricular node

Anterior fascicle of left bundle branch

Right bundle branch

Posterior fascicle of left bundle branch Figure 3-3 Schematic representation of the cardiac conduction system. Purkinje fibers

toward the posteromedial papillary muscle. Both the right and the left bundle branches terminate in Purkinje cells, which are large cells with well-developed intercellular connections that allow for the rapid propagation of electrical impulses. These impulse-generating cells then directly stimulate myocytes. Heart blocks, a form of cardiac arrhythmia, may arise from intrinsic problems of the conduction system or from impaired blood supply (coronary artery disease) to the conduction system. The SA node is supplied by the SA nodal artery, which is a branch of the RCA in about 60% of the population or a branch of the LCx in 40%. The AV node is supplied by the AV nodal artery, which is a branch of the RCA in about 90% of the population or a branch of the LCx in 10%. The right bundle branch receives most of its blood supply from septal perforators that branch off of the LAD. There may also be collateral blood supply from the RCA or LCx. The left anterior fascicle is supplied by septal perforators from the LAD and is particularly susceptible to ischemia and infarction. The proximal portion of the left posterior fascicle is supplied by the AV nodal artery and by septal perforators of the LAD. The distal portion of the posterior fascicle has a dual blood supply from anterior and posterior septal perforators (i.e., the LAD and PDA).

Neural Innervation The normal myocardium is richly innervated by the autonomic nervous system. The sympathetic supply is from preganglionic neurons located within the superior five to six thoracic segments of the spinal cord, which synapse with second-order neurons in the cervical sympathetic ganglia. Traveling within the cardiac nerves, these fibers end in the SA node, AV node, epicardial vessels, and myocardium. The parasympathetic supply is from preganglionic neurons originating in the dorsal motor nucleus of the medulla and pass as branches of the vagus nerve to the heart. Here the fibers synapse with second-order neurons located in ganglia within the heart. Nerve terminals of the parasympathetic nerves end in the SA node, AV node, epicardial vessels, and myocar-

Chapter 3—Structure and Function of the Normal Heart and Blood Vessels dium. A supply of vagal afferents from the inferior and posterior aspects of the ventricles mediate important cardiac reflexes, whereas the vagal efferent fibers to the SA and AV nodes are active in modulating impulse initiation and conduction. In general, sympathetic stimulation increases heart rate (HR) and force of myocardial contraction, and parasympathetic stimulation slows HR and reduces the force of contraction.

I band (actin)

A band (actin and myosin)

Z line

H zone (myosin)

25

Z line

Myocardium Cardiac tissue (myocardium) is composed of several cell types that together produce the organized contraction of the heart. Specialized myocardial cells make up the cardiac electrical system (conduction system) and are responsible for the generation of an electrical impulse and organized propagation of that impulse to cardiac muscle fibers (myocytes), which, in turn, respond by mechanical contraction. Atrial and ventricular myocytes are specialized, branching muscle cells connected end to end by intercalated disks. These thickened regions of the cell membrane (sarcolemma) aid in the transmission of mechanical tension between cells. The sarcolemma has functions similar to those of other cell membranes, including maintenance of ionic gradients, propagation of electrical impulses, and provision of receptors for neural and hormonal inputs. In addition, the sarcolemma is intimately involved with the coupling of myocardial excitation and contraction through small transverse tubules (T tubules) that extend from the sarcolemma into the intracellular space. The myocytes contain several other organelles: the nucleus; the multiple mitochondria responsible for generating the energy required for contraction; an extensive network of intracellular tubules called the sarcoplasmic reticulum, which functions as the major intracellular storage site for calcium; and the myofibrils, which are the contractile elements of the cell. Each myofibril is made up of repeating units called sarcomeres, which are, in turn, composed of overlapping thin actin filaments and thick myosin filaments and their regulatory proteins troponin and tropomyosin (Fig. 3-4).

Muscle Physiology and Contraction Contraction of myocytes begins with electrical depolarization of the sarcolemma, resulting in an influx of calcium into the cell through channels in the T tubules (Fig. 3-5). This initial calcium entry stimulates the rapid release of large amounts of calcium from the sarcoplasmic reticulum into the cell cytosol. The calcium then binds to the calciumbinding troponin subunit (troponin C) on the actin filaments of the sarcomere, resulting in a conformational change in the troponin-tropomyosin complex. This change facilitates the actin-myosin interaction, which results in cellular contraction. As the wave of depolarization passes, the calcium is rapidly and actively resequestered in the sarcoplasmic reticulum, where it is stored by various proteins, including calsequestrin, until the next wave of depolarization occurs. Calcium is also extruded from the cytosol by

A M line Sarcomere

Myosin

Actin

B Figure 3-4 A, Sarcomere as it appears under the electron microscope. B, Schematic of the location and interaction of actin and myosin.

various calcium pumps in the sarcolemma. The force of myocyte contraction can be regulated by the amount of free calcium released into the cell by the sarcoplasmic reticulum. More calcium allows for greater actin-myosin interaction, producing a stronger contraction. The energy for myocyte contraction is derived from adenosine triphosphate (ATP), which is generated by oxidative phosphorylation of adenosine diphosphate (ADP) in the abundant mitochondria of the cell. ATP is required both for calcium influx and for force generation by actin-myosin interaction. During contraction, ATP promotes dissociation of myosin from actin, thereby permitting the sliding of thick filaments past thin filaments as the sarcomere shortens. Under normal circumstances, fatty acids are the preferred energy source, although glucose can also be used as a substrate. These substrates must be constantly delivered to the heart through the bloodstream because minimal energy is stored in the heart. Myocardial metabolism is aerobic and thus requires a constant supply of oxygen. Under ischemic or hypoxemic conditions, glycolysis and lactate may serve as a source of ATP, although in insufficient quantities to sustain the working heart. Ischemic conditions might also promote alterations in both cytosolic and mitochondrial calcium overload, a major terminal event in muscle injury of the heart, termed myocardial infarction.

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Depolarization

Repolarization Na+-Ca2+ exchange pump

SR

Ca2+

Ca2+

SR Ca2+ ATPase

Na+ Ca2+ release

Na+

Ca2+ storage

T tubule Ca2+

Ca2+

Ca2+

ATP Myosin

M

M

ATP

Ca2+-ATPase

Actin

Figure 3-5 Calcium dependence of myocardial contraction. (1) Electrical depolarization of the myocyte results in an influx of Ca2+ into the cell through channels in the T tubules. (2) This initial phase of calcium entry stimulates the release of large amounts of Ca2+ from the sarcoplasmic reticulum (SR). (3) The Ca2+ then binds to the troponin-tropomyosin complex on the actin filaments, resulting in a conformational change that facilitates the binding interaction between actin and myosin. In the presence of adenosine triphosphate (ATP), the actin-myosin association is cyclically dissociated as the thick and thin filaments slide past each other, resulting in contraction. (4) During repolarization, the Ca2+ is actively pumped out of the cytosol and sequestered in the SR. M, mitochondrion.

Circulatory Physiology and the Cardiac Cycle The cardiac cycle is a repeating series of contractile and valvular events during which the valves open and close in response to pressure gradients between different cardiac chambers (Fig. 3-6). This cycle can be divided into systole, the period of ventricular contraction, and diastole, the period of ventricular relaxation. With the onset of ventricular contraction, the pressure in the ventricles increases and exceeds that in the atria, at which time the AV valves close. Intraventricular pressure continues to rise, initially without a change in ventricular volume (isovolumic contraction), until the intraventricular pressures exceed the pressures in the aorta and pulmonary artery, at which time the semilunar valves open and ventricular ejection of blood occurs. With the onset of ventricular relaxation, the pressure in the ventricles falls until the pressure in the arterial chambers exceeds that

in the ventricles, and the semilunar valves close. Ventricular relaxation continues, initially without a change in ventricular volume (isovolumic relaxation). When the pressure in the ventricles falls below the pressure in the atria, the AV valves open, and a rapid phase of ventricular filling occurs as blood in the atria empties into the ventricles. At the end of diastole, active atrial contraction augments ventricular filling. This augmentation is particularly important in patients with poor ventricular function or stiff ventricles and is lost in patients with atrial fibrillation. In the absence of valvular disease, no impediment to the flow of blood exists from the ventricles to the arterial beds, and the systolic arterial pressure rises sharply to a peak. During diastole, the arterial pressure gradually falls as blood flows distally, and elastic recoil of the arteries occurs. This response contrasts with the pressure response in the ventricles during diastole, in which pressure gradually increases as blood enters the ventricles from the atria. Atrial pressure can be directly measured in the right atrium, whereas occluding

Chapter 3—Structure and Function of the Normal Heart and Blood Vessels Systole

Diastole

Table 3-1 Normal Values for Common Hemodynamic Parameters

120

Heart Rate Pressure (mm Hg)

60-100 Beats/Minute

Pressures

100 AVO

Aorta

80 60 40 20

27

Left ventricle

MVO v

LA a

LV

0

c

4 1

2

Jugular pulse a

ECG P 0.0

0.1

c

Q

R

y

x

S

0.2 0.3

x

Heart sounds

3 v

y

Systemic vascular resistance Pulmonary vascular resistance Cardiac output Cardiac index 0.5

0.6

≤9 mm Hg ≤9 mm Hg 15-30 mm Hg ≤9 mm Hg 15-30 mm Hg 3-12 mm Hg ≤12 mm Hg ≤12 mm Hg 100-140 mm Hg 3-12 mm Hg 100-140 mm Hg 60-90 mm Hg

Resistance

T 0.4

Central venous Right atrial Right ventricular Systolic End-diastolic Pulmonary arterial Systolic Diastolic Pulmonary capillary wedge Left atrial Left ventricular Systolic End-diastolic Aortic Systolic Diastolic

800-1500 dynes-sec/cm−5 30-120 dynes-sec/cm−5 4-6 L/min 2.5-4 L/min

0.7

Isovolumic contraction

Isovolumic relaxation Time (sec) Figure 3-6 Simultaneous electrocardiogram (ECG) and pressure tracings obtained from the left atrium (LA), left ventricle (LV), and aorta, and the jugular venous pressure during the cardiac cycle. For simplification, right-sided pressures have been omitted. Normal right atrial pressure closely parallels that of the left atrium, and right ventricular and pulmonary artery pressures are timed closely with their corresponding left-sided heart counterparts; they are reduced only in magnitude. The normal mitral and aortic valve closure precedes tricuspid and pulmonic valve closure, respectively, whereas valve opening reverses this order. The jugular venous pulse lags behind the right atrial pulse. During the course of one cardiac cycle, the electrical events (ECG) initiate and therefore precede the mechanical (pressure) events, and the latter precedes the auscultatory events (heart sounds) they themselves produce. Shortly after the P wave, the atria contract to produce the a wave. The QRS complex initiates ventricular systole, followed shortly by LV contraction and the rapid buildup of LV pressure. Almost immediately, LV pressure exceeds LA pressure, closing the mitral valve and producing the first heart sound. After a brief period of isovolumic contraction, LV pressure exceeds aortic pressure and the aortic valve opens (AVO). When the ventricular pressure once again falls below the aortic pressure, and the aortic valve closes to produce the second heart sound and terminate ventricular ejection. The LV pressure decreases during the period of isovolumic relaxation until it drops below LA pressure, and the mitral valve opens (MVO).

a small pulmonary artery branch and measuring the pressure distally (the pulmonary capillary wedge pressure) is often used to obtain left atrial pressure indirectly. An atrial pressure tracing is shown in Figure 3-6 and is composed of several waves. The a wave represents atrial contraction. As

the atria subsequently relax, the atrial pressure falls, and the x descent is noted on the pressure tracing. The x descent is interrupted by a small c wave, which is generated as the AV valve bulges toward the atrium during ventricular systole. As the atria fill from venous return, the v wave is seen, after which the y descent appears as the AV valves open and blood from the atria empties into the ventricles. The normal ranges of pressures in the various cardiac chambers are shown in Table 3-1.

CARDIAC PERFORMANCE The amount of blood ejected by the heart each minute is referred to as the cardiac output (CO) and is the product of the stroke volume (SV; amount of blood ejected with each ventricular contraction) and the HR: CO = SV × HR The cardiac index is the CO divided by the body surface area; it is measured in liters per minute per square meter and is a way of normalizing CO to body size. The normal CO at rest is 4 to 6 L/min, although this value can increase fourfold to sixfold during strenuous exercise as a result of increases in HR (chronotropic) and SV (inotropic). The SV is a measure of the mechanical function of the heart and is affected by preload, afterload, and contractility (Table 3-2). Preload is the volume of blood in the ventricle at the end of diastole and is primarily a reflection of venous return. Within limits, as the preload increases, the ventricle stretches, and the ensuing ventricular contraction becomes more rapid and forceful. This phenomenon is known as the

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Table 3-2 Factors Affecting Cardiac Performance Preload (left ventricular diastolic volume)

Afterload (impedance against which the left ventricle must eject blood)

Contractility (cardiac performance independent of preload or afterload)

Heart rate

Total blood volume Venous (sympathetic) tone Body position Intrathoracic and intrapericardial pressures Atrial contraction Pumping action of skeletal muscle Peripheral vascular resistance Left ventricular volume (preload, wall tension) Physical characteristics of the arterial tree (elasticity of vessels or presence of outflow obstruction) Sympathetic nerve impulses Increased contractility Circulating catecholamines Digitalis, calcium, other inotropic agents Increased heart rate or post-extrasystolic augmentation Anoxia, acidosis Decreased contractility Pharmacologic depression Loss of myocardium Intrinsic depression Autonomic nervous system Temperature, metabolic rate Medications, drugs

Frank-Starling relationship. Because ventricular volume is not easily measured, ventricular filling pressure (ventricular end-diastolic pressure, atrial pressure, or pulmonary capillary wedge pressure) is frequently used as a surrogate measure of preload. Two major means can manipulate the preload in a clinical setting. The first is to modulate volume status: intravenous fluids to increase preload and diuretics to decrease preload. The second is to regulate vascular tone: nitroglycerin to diminish preload. Afterload is the force against which the ventricles must contract to eject blood. The arterial pressure is often used as a practical measure of afterload; although, in truth, the intraventricular pressure, the size of the ventricular cavity, and the thickness of the ventricular walls (Laplace’s law) determine afterload. Thus, afterload is increased in the setting of systemic hypertension or stenosis of the aortic valve but may be equally increased in the setting of ventricular dilation or ventricular hypertrophy. Some antihypertensive drugs, such as angiotensin-converting enzyme (ACE) inhibitors and hydralazine, reduce blood pressure (BP) by reducing afterload. Contractility, or inotropy, although difficult to define, represents the force of ventricular contraction independent of loading conditions. For example, an increase in contractility results in a stronger ventricular contraction even when

the preload and afterload are kept constant. Direct stimulation from adrenergic nerves in the myocardium and circulating catecholamines released from the adrenal glands can alter contractility under normal conditions. Several medications have important positive inotropic effects that can be exploited clinically, including digoxin and the sympathomimetic amines (e.g., epinephrine, norepinephrine, dopamine). Other medications, many of them antihypertensive medications, (e.g., β blockers, calcium channel antagonists) have negative inotropic effects and can decrease the strength of ventricular contraction. Overall ventricular systolic function is frequently quantified by the ejection fraction, which is the ratio of the SV to the end-diastolic volume, that is, the fraction of blood in the ventricle ejected with each ventricular contraction. The normal ejection fraction is about 60% and can be measured by invasive (contrast ventriculography) or noninvasive (echocardiography or radionuclide ventriculography) methods. Clearly, systolic contraction is an important component of ventricular function; however, ventricular diastolic relaxation (lusitropy) also plays an important role in overall cardiac performance. Impaired relaxation (diastolic dysfunction), as occurs with ventricular hypertrophy or ischemia, results in a stiff, noncompliant ventricle, leading to impaired ventricular filling and an increased ventricular pressure for any given diastolic volume.

PHYSIOLOGY OF THE CORONARY CIRCULATION The heart is an aerobic organ requiring a constant supply of oxygen to maintain normal function. Under normal conditions, the supply of oxygen delivered to the heart is closely matched to the amount of oxygen required by the heart (the myocardial oxygen consumption [Mvo2]). The main determinants of Mvo2 are HR, contractility, and wall stress. The wall stress, as determined by Laplace’s law, is directly related to the systolic pressure and the heart size and inversely proportional to wall thickness: Wall stress = ( pressure × radius ) (2 × wall thickness ) Thus, the Mvo2 parallels changes in HR, BP, contractility, and heart size. In general, oxygen delivery to an organ can be augmented by either increasing blood flow or increasing oxygen extraction from the blood. For all practical purposes, the oxygen extraction by the heart is maximal at rest, and thus increases in coronary blood flow must meet increases in Mvo2. Because of the compression of intramyocardial blood vessels during systole, most coronary flow occurs during diastole. Therefore, diastolic pressure is the major pressure driving the coronary circulation. An important implication of this fact is that tachycardia, which primarily shortens the duration of diastole, results in reduced time for coronary flow, which occurs despite the increase in Mvo2 associated with increased HR. The systolic pressure has little effect on coronary blood flow except insofar as changes in BP lead to changes in Mvo2. Regulation of coronary blood flow occurs primarily through changes in coronary vascular resistance. In response

Chapter 3—Structure and Function of the Normal Heart and Blood Vessels to a change in Mvo2, the coronary arteries can dilate or constrict to allow for appropriate changes in coronary flow. Additionally, in the range of coronary perfusion pressures of 60 to 130 mm Hg, coronary blood flow is held constant by the process of autoregulation of the coronary arteries. This regulation of arterial resistance occurs at the level of the arterioles and is mediated by several factors. As ATP is metabolized during increased myocardial activity, adenosine is released and acts as a potent vasodilator. Decreased oxygen tension, increased carbon dioxide, acidosis, and hyperkalemia all develop during increased myocardial metabolism and may also mediate coronary vasodilation. The coronary arteries are innervated by the autonomic nervous system, and activation of sympathetic or parasympathetic neurons alters coronary blood flow by affecting changes in vascular tone. Parasympathetic innervation through the vagus nerve and through the neurotransmitter acetylcholine results in vasodilation. Sympathetic neurons use norepinephrine as a neurotransmitter and may have opposing effects on the coronary vasculature. Stimulation of α receptors results in vasoconstriction, whereas stimulation of β receptors leads to vasodilation. The ability of the coronary vasculature to mediate changes in blood flow through changes in vascular tone depends in large part on an intact, normally functioning endothelium. The endothelium produces several potent vasodilators, including endothelium-derived relaxing factor (EDRF) and prostacyclin. EDRF is likely to be nitric oxide or a compound containing nitric oxide and is released by the endothelium in response to acetylcholine, thrombin, ADP, serotonin, bradykinin, platelet aggregation, and an increase in shear stress. The latter stimulus accounts for the dilation of the coronary arteries in response to increases in blood flow in the setting of increases in Mvo2 (called flow-dependent vasodilation). Vasoconstricting factors, most notably endothelin, are also produced by the endothelium and are likely to play a role in regulating vascular tone. The balance of these vaso dilator and vasoconstriction factors may be important in conditions such as coronary vasospasm. In addition to influencing vascular tone, the endothelium has several other functions that have important implications for blood flow and tissue perfusion. These include maintenance of a nonthrombotic surface through inhibition of platelet activity, control of thrombosis and fibrinolysis, and modulation of the inflammatory response of the vasculature. Disturbances in these normal properties of the endothelium (endothelial dysfunction) are likely to play an important role in the pathophysiologic conditions of coronary atherosclerosis and thrombosis.

PHYSIOLOGY OF THE SYSTEMIC CIRCULATION The normal cardiovascular system is capable of providing appropriate blood flow to each of the organs and tissues of the body under a wide range of conditions. This is achieved by maintaining arterial BP within normal limits to meet functional needs from adjustments to the cardiac output and the resistance to blood flow in specific organs and tissues. Arterial pressure is regulated acutely and chronically through various local and systemic, humoral, and neural factors.

29

Poiseuille’s law describes the relationship between pressure and flow. Although not exactly descriptive of blood flow through elastic tapering blood vessels, Poiseuille’s law is useful in understanding blood flow. Fluid flow (F) through a tube is proportional (proportionality constant = K) to the pressure (P) difference between the ends of the tube: F = K × ∆P The reciprocal of K is the resistance to flow (R); that is K = 1/R. When fluid flows through a tube, the resistance to flow is determined by the properties of both the fluid and the tube. In the case of a steady, streamlined flow of fluid through a rigid tube, Poiseuille found that these factors determine resistance: R = 8ηL πr 4 where r is the radius of the tube, L is its length, and η is the viscosity of the fluid. This equation shows that the resistance to blood flow increases proportionately with increases in fluid viscosity or tube length. In contrast, radius changes have a much greater influence because resistance is inversely proportional to the fourth power of the radius. Poiseuille’s law incorporates the factors influencing flow, so that: F = ∆P R = ∆Pπr 4 8ηL The most important determinants of blood flow in the cardiovascular system are ΔP and r4. Thus, small changes in arterial radius can cause large changes in flow to a tissue or organ. Systemic vascular resistance (SVR) is the total resistance of flow offered by the blood vessels of the systemic circulation. Physiologic changes in SVR are primarily caused by changes in the radius of small arteries and arterioles, the resistance vessels of the systemic circulation. The SVR is defined as the pressure drop across the peripheral capillary beds divided by the blood flow across the beds (e.g., SVR = BP/CO). In practice, this is calculated as the mean arterial pressure minus the right atrial pressure divided by the cardiac output and is normally in the range of 800 to 1500 dynes sec/cm5. As with the coronary circulation autonomic innervation alters systemic vascular tone through sympathetic and parasympathetic innervation. Local oxygen tension, carbon dioxide levels, pH, and potassium levels have direct effects on vascular tone and blood flow. And finally, a normally functioning endothelium mediates changes in blood flow through potent vasodilatory and vasoconstricting factors (see “Physiology of the Coronary Circulation”). Control of BP through neural regulation occurs by means of tonic and reflexive modulation of autonomic nervous system outflow. Acutely, changes in these outflows influence key determinants of BP, such as cardiac chronotropy, inotropy, and vascular resistance. The primary mechanism by which BP is neurally modulated is through the baroreflexes. The baroreflex loop anatomically originates at the level of the baroreceptor. The baroreceptors are highly specialized stretch-sensitive nerve endings distributed throughout various regions of the cardiovascular systems, such as the

30


carotid artery, aorta, and the cardiopulmonary region. Baroreceptors located in the carotid artery (e.g., carotid sinus) and aorta are sometimes referred to as high-pressure baroreceptors and those in the cardiopulmonary areas as lowpressure baroreceptors. After transmission of afferent impulses to the central nervous system, signals are integrated, and the efferent arm of the reflex projects neural signals systemically through the sympathetic and parasympathetic branches of the autonomic nervous system. In general, in response to an increase in systemic BP, there is an increased firing rate of the baroreceptors, efferent sympathetic outflow is inhibited (reducing vascular tone, chronotropy, and inotropy), and parasympathetic outflow is increased (reducing cardiac chronotropy). The opposite occurs when BP decreases. Cardiac output and systemic BP are controlled not only neurally and by local vasoactive substances through regulation of vascular tone but also by blood volume. A major physiologic control mechanism, which regulates total blood volume, is the renin-angiotensin-aldosterone system (RAAS). Renin is an enzyme secreted by the kidneys in response to low renal perfusion, low blood volume, low BP, or low sodium concentration. Renin converts the polypeptide angiotensinogen to angiotensin I in the liver. Angiotensin I circulates in the bloodstream and is converted to angiotensin II by the activity of ACE located primarily in the capillary beds of the lung. Angiotensin II is a powerful vasoconstrictor regulating BP through changes in vascular tone. In addition to its vasoactive properties, angiotensin II activates release of the hormone aldosterone from the adrenal cortex. Aldosterone then acts on the kidneys to retain sodium and thus water. Angiotensin II also acts directly on the posterior pituitary gland, increasing the secretion of vasopressin (e.g., antidiuretic hormone). Much like angiotensin II, vasopressin is a vasoconstrictor; it also acts on the kidney by retaining water through its action on V2 receptors in the collecting ducts. Although activity of the RAAS is to maintain blood volume, this system has adverse effects in chronic disease states, aggravating conditions such as hypertension and heart failure. Blood leaves the arterioles and flows into the capillary systems, where oxygen and nutrients are delivered to cells and carbon dioxide and metabolic wastes are removed. The deoxygenated blood then drains into peripheral veins, which contain valves to prevent backflow. These veins have thinner walls than arteries and function as capacitance vessels; they are able to accommodate a significantly larger volume of blood than the arterial system. With the aid of the pumping action of skeletal muscles and the respiratory motion of the chest wall, blood returns to the right atrium. This venous return can be altered by constriction or dilation of the peripheral veins. In addition to the venous drainage, a rich system of lymphatic vessels helps drain excess interstitial fluid from the periphery. The various lymphatic vessels drain into the thoracic duct and, subsequently, into the left brachiocephalic vein.

PHYSIOLOGY OF THE PULMONARY CIRCULATION Similar to the systemic circulation, the pulmonary circulation consists of a branching network of progressively smaller arteries, arterioles, capillaries, and veins. The pulmonary

capillaries are separated from the alveoli by a thin alveolarcapillary membrane through which gas exchange occurs. Carbon dioxide thus diffuses from the capillary blood into the alveoli, and oxygen diffuses from the alveoli into the blood. The flow of blood to various lung segments is regulated by several factors, the most important being the Po2 in the alveoli. In this manner, blood is shunted toward wellventilated lung segments and away from poorly ventilated segments. As a result of the extensive nature of the pulmonary capillary system and the distensibility of the pulmonary vasculature, the resistance across the pulmonary system (the pulmonary vascular resistance) is about 10% that of the systemic circulation. Owing to these features, the pulmonary system is able to tolerate significant increases in blood flow with little or no rise in pulmonary pressure. Thus, intracardiac shunts (e.g., atrial septal defects) may be associated with normal pulmonary pressure. The lung receives a dual blood supply. The pulmonary artery accounts for most pulmonary blood flow; however, the lungs also receive oxygenated blood through the bronchial arteries. These vessels supply oxygen to the lung and drain into the bronchial veins. The bronchial veins drain partly into the pulmonary veins; thus, a small amount of deoxygenated blood normally enters the systemic circulation and accounts for a physiologic right-to-left shunt. In the normal setting, this shunt is insignificant, accounting for only 1% of the total systemic blood flow.

Cardiovascular Response to Exercise The response of the heart to exercise is multifaceted and involves many of the previously discussed mechanisms of circulatory control (Table 3-3). In anticipation of exercise, neural centers in the brain stimulate vagal withdrawal and an increase in sympathetic tone, resulting in an increase

Table 3-3 Physiologic Responses to Exercise Increased heart rate Increased stroke volume Increased contractility Increased venous return

Decreased afterload Increased blood pressure

Increased O2 extraction

Increased sympathetic stimulation Decreased parasympathetic stimulation Increased sympathetic stimulation Sympathetic-mediated venoconstriction Pumping action of skeletal muscles Decreased intrathoracic pressure with deep inspirations Arteriolar vasodilation in exercising muscle Arteriolar vasodilation in exercising muscle (mediated chiefly by local metabolites) Increased cardiac output Vasoconstriction (sympathetic stimulation) on nonexercising vascular beds Shift in oxyhemoglobin dissociation curve as a result of local acidosis

Chapter 3—Structure and Function of the Normal Heart and Blood Vessels in HR and contractility (thus an increase in CO) before exercise ever starts. With exercise, sympathetic venoconstriction, augmented pumping action of skeletal muscles, and increased respiratory movements of the chest wall result in an increase in venous return to the heart. Through the Frank-Starling relationship, this increase in venous return results in an increase in contractility, thus augmenting CO. Sympathetic activation may also increase contractility; however, most of the increase in CO during exercise (up to 4 to 6 times the normal rate) is a consequence of an increase in HR. The peak HR that can be achieved is dependent on age and can be estimated by the following formula: maximal HR = (220 − age) ± 15 beats/minute. Local factors in exercising muscle cause arteriolar dilation, resulting in increased flow to the capillary beds. This vasodilation results in decreased resistance to flow, and

31

therefore the SVR decreases with exercise. Despite this change in resistance, the systolic BP rises, owing to the augmented CO and to sympathetic vasoconstriction, which leads to the preferential shunting of blood away from nonexercising vascular beds. The diastolic BP, by contrast, generally remains constant during exercise. The pulmonary system is able to tolerate the increased flow with only small increases in pulmonary pressure. The increases in HR and contractility result in a significant increase in Mvo2 (up to 300%), and coronary blood flow subsequently increases. Various types of exercises have different effects on the circulatory system. The response described in this text occurs with isotonic exercises, such as running or biking. With isometric exercises, such as weight lifting, the predominant response is an increase in BP, owing to an increase in peripheral vasoconstriction.

Prospectus for the Future Recent years have witnessed an explosion in the growth of basic knowledge governing normal heart development and function of the circulatory system. New insights about the molecular switches and factors that promote the formation of heart chambers and blood vessels are unraveling the genetic basis for unusual causes of congenital heart disease. Similarly, the recent discovery of specific growth factors and

References Berne RM, Levy MN: Physiology, Updated Edition, 5th ed., with Student Consult Access. Part IV: The Cardiovascular System. St Louis, Elsevier, 2004. Guyton AC, Hall JE: Textbook of Medical Physiology. St. Louis, Elsevier, 2005.

signaling pathways that guide vascular trajectory and ensure vascular stability offer new opportunities to rethink future strategies for promoting cardiac and vascular regeneration and repair. With increasing refinement in this basic knowledge, future milestones appear on the horizon for diagnosis, early treatment, and even prevention of cardiovascular diseases.

III

Chapter

4

Evaluation of the Patient with Cardiovascular Disease Sheldon E. Litwin and Ivor J. Benjamin

History As with diseases of most organ systems, the ability of the physician to diagnose diseases of the cardiovascular system is in large part dependent on eliciting and interpreting the patient’s clinical history. A thorough history can enable the physician to identify a patient’s symptoms as characteristic of a specific cardiovascular disorder or to suggest that symptoms are unlikely to be caused by cardiovascular disease. In addition, a complete history will reveal the presence of other systemic diseases that may have cardiovascular manifestations, identify existing risk factors that may be modified to prevent the future development of cardiovascular disease (see Chapter 9), enable the selection of appropriate further diagnostic testing (see Chapter 5), and allow the assessment of functional capacity and extent of cardiovascular disability. The patient should be asked about prior medical conditions, including childhood illnesses (e.g., rheumatic fever), as well as intravenous drug use, which may lead to the development of valvular heart disease. Several cardiovascular disorders are inherited (e.g., hypertrophic cardiomyopathy, Marfan syndrome, long QT syndrome), and a thorough family history may bring this potential to the examiner’s attention. The classic symptoms of cardiac disease include precordial discomfort or pain, dyspnea, palpitations, syncope or presyncope, and edema. Although characteristic of heart disease, these symptoms are nonspecific and may also occur as a result of diseases of other organ systems (e.g., musculoskeletal, pulmonary, renal, gastrointestinal). Furthermore, some patients with established cardiovascular disease may be asymptomatic or have atypical symptoms. Chest pain is a frequent symptom and may be a manifestation of cardiovascular or noncardiovascular disease (Tables 4-1 and 4-2). Full characterization of the pain with regard 32

to quality, quantity, frequency, location, duration, radiation, aggravating or alleviating factors, and associated symptoms may help distinguish among various causes. Reversible myocardial ischemia caused by obstructive coronary artery disease commonly results in episodic chest pain or discomfort during exertion or stress (angina pectoris). Patients frequently deny having pain and, instead, describe a discomfort in their chest. Sometimes they will refer to the discomfort as a squeezing, tightening, pressing, or burning sensation or as a heavy weight on their chest, and they will sometimes clench their fist over their chest while describing the discomfort (Levine sign). Anginal discomfort is classically located substernally or over the left chest. It frequently radiates to the epigastrium, neck, jaw, or back and down the ulnar aspect of the left arm. Radiation to the right chest or arm is less common, whereas radiation above the jaw or below the epigastrium is not typical of cardiac disease. Angina is usually brought on by either physical or emotional stress, is mild to moderate in intensity, lasts 2 to 10 minutes, and resolves with rest or sublingual administration of nitroglycerin. It may occur more frequently in the morning, in cold weather, after a large meal, or after exposure to environmental factors, including cigarette smoke, and is frequently accompanied by other symptoms, such as dyspnea, diaphoresis, nausea, palpitations, or lightheadedness. Patients frequently report a stable pattern of angina that is predictably reproducible with a given amount of exertion. Unstable angina occurs when a patient reports a significant increase in the frequency or severity of angina or when angina occurs with progressively decreasing exertion or at rest. When anginal-type pain occurs mainly at rest, it may be of a noncardiac origin, or it may reflect true cardiac ischemia resulting from coronary spasm (Prinzmetal or variant angina). The pain of an acute myocardial infarction may be similar

Chapter 4—Evaluation of the Patient with Cardiovascular Disease

33

Table 4-1 Cardiovascular Causes of Chest Pain Aggravating or Alleviating Factors

Condition

Location

Quality

Duration

Angina

Retrosternal region: radiates to or occasionally isolated to neck, jaw, shoulders, arms (usually left), or epigastrium

Pressure, squeezing, tightness, heaviness, burning, indigestion

30 minutes). The pain of acute pericarditis is usually sharper than anginal pain, is located to the left of the sternum, and may radiate to the neck or left shoulder. In contrast to angina, the pain may last hours, typically worsens with inspiration, and improves when the patient sits up and leans forward; it may be associated with a pericardial friction rub. Acute aortic dissection produces severe, sharp, tearing pain that radiates to the back and may be associated with asymmetrical pulses and a murmur of aortic insufficiency. Pulmonary emboli may produce the sudden onset of sharp chest pain that is worse on inspiration, is associated with shortness of breath, and may have an associated pleural friction rub, especially if a pulmonary infarction is present. A multitude of noncardiac conditions may also produce chest pain (see Table 4-2). The clinical history and physical examination findings will often help distinguish these causes from ischemic chest pain. Dyspnea, an uncomfortable, heightened awareness of breathing, is commonly a symptom of cardiac disease. Patients with decreased left ventricular function may exhibit significant abnormalities of the aortic or mitral valves or decreased myocardial compliance (i.e., left ventricular hypertrophy, acute ischemia), left ventricular diastolic, or left atrial pressure increases transmitted through the pulmonary veins to the pulmonary capillary system, producing vascular congestion. This congestion results in exudation of fluid into the alveolar space and impairs gas exchange across the alveolar-capillary membrane, producing the subjective

Precipitated by exertion, cold weather, or emotional stress; relieved by rest or nitroglycerin; variant (Prinzmetal) angina may be unrelated to exertion, often early in the morning Unrelieved by rest or nitroglycerin

Associated Symptoms or Signs Dyspnea; S3, S4, or murmur of papillary dysfunction during pain

Dyspnea, nausea, vomiting, weakness, diaphoresis Pericardial friction rub

Murmur of aortic insufficiency; pulse or blood pressure asymmetry; neurologic deficit

sensation of dyspnea. Dyspnea frequently occurs on exertion; however, in patients with severe cardiac disease, it may be present at rest. Patients with heart failure commonly sleep on two or more pillows because the augmented venous return that occurs on assuming the recumbent position produces an increase in dyspnea (orthopnea). In addition, these patients report awakening 2 to 4 hours after the onset of sleep with dyspnea (paroxysmal nocturnal dyspnea), which is likely caused by the central redistribution of peripheral edema in the supine position. Dyspnea may be associated with diseases of the lungs or chest wall and is also seen in anemia, obesity, deconditioning, and anxiety disorders. In addition, the sudden onset of dyspnea, with or without chest pain, may be present with pulmonary emboli. It is frequently difficult to distinguish cardiac from pulmonary causes of dyspnea by history alone because both may produce resting or exertional dyspnea, orthopnea, or cough. Wheezing and hemoptysis are classically results of pulmonary disease, although they are also frequently present in the patient with pulmonary edema resulting from left ventricular dysfunction or mitral stenosis. True paroxysmal nocturnal dyspnea is, however, more specific for cardiac disease. In patients with coronary artery disease, dyspnea may be an anginal equivalent; that is, the dyspnea is the result of ischemia and occurs in a pattern consistent with angina but in the absence of chest discomfort. Palpitation refers to the subjective sensation of the heart beating. Patients may describe a fluttering or pounding in the chest or a feeling that their heart races or skips a beat. Some

34


Table 4-2 Noncardiac Causes of Chest Pain Aggravating or Alleviating Factors

Condition

Location

Quality

Duration

Pulmonary embolism (chest pain often not present)

Substernal or over region of pulmonary infarction

Pleuritic (with pulmonary infarction) or angina-like

Sudden onset (minutes to hours)

Aggravated by deep breathing

Pulmonary hypertension

Substernal

Pressure; oppressive

—

Aggravated by effort

Pneumonia with pleurisy

Located over involved area

Pleuritic

—

Aggravated by breathing

Spontaneous pneumothorax

Unilateral

Sharp, well localized

Sudden onset; lasts many hours

Aggravated by breathing

Musculoskeletal disorders

Variable

Aching, well localized

Variable

Herpes zoster

Dermatomal distribution Substernal or epigastric; may radiate to neck

Sharp, burning

Prolonged

Aggravated by movement; history of exertion or injury None

Burning, visceral discomfort

10-60 min

Peptic ulcer

Epigastric, substernal

Prolonged

Gallbladder disease

Right upper quadrant; epigastric Often localized over precordium

Visceral burning, aching Visceral

Prolonged

Spontaneous or following meals

Variable; location often moves from place to place

Varies; often fleeting

Situational

Esophageal reflux

Anxiety states

people feel post-extrasystolic beats as a painful or uncomfortable sensation. Common arrhythmic causes of palpitations include premature atrial or ventricular contractions, supraventricular tachycardia, ventricular tachycardia, and sinus tachycardia. Occasionally, patients report palpitations even when no rhythm disturbance is noted during monitoring, as occurs commonly in patients with anxiety disorders. The pattern of palpitations, especially when correlated to the pulse, may help narrow the differential diagnosis: rapid, regular palpitations are noted with supraventricular tachycardia or ventricular tachycardia; rapid, irregular palpita-

Aggravated by large meal, postprandial recumbency; relief with antacid Relief with food, antacid

Associated Symptoms or Signs Dyspnea, tachypnea, tachycardia; hypotension, signs of acute right ventricular heart failure, and pulmonary hypertension with large emboli; pleural rub; hemoptysis with pulmonary infarction Pain usually associated with dyspnea; signs of pulmonary hypertension Dyspnea, cough, fever, bronchial breath sounds, rhonchi, egophony, dullness to percussion, occasional pleural rub Dyspnea; hyperresonance and decreased breath and voice sounds over involved lung Tender to palpation or with light pressure

Vesicular rash appears in area of discomfort Water brash

— Right upper quadrant tenderness may be present Sighing respirations; often chest wall tenderness

tions are noted with atrial fibrillation; and skipped beats are noted with premature atrial or ventricular contractions. Syncope is the transient loss of consciousness resulting from inadequate cerebral blood flow and may be the result of a variety of cardiovascular diseases (see Chapter 10). True syncope must be distinguished from primary neurologic causes of loss of consciousness (i.e., seizures) and metabolic causes of loss of consciousness (e.g., hypoglycemia, hyperventilation). Cardiac syncope occurs after an abrupt decrease in cardiac output, as may occur with acute myocardial ischemia, valvular heart disease (aortic or mitral stenosis),

Chapter 4—Evaluation of the Patient with Cardiovascular Disease hypertrophic obstructive cardiomyopathy, left atrial tumors, tachyarrhythmias (ventricular, or less commonly supraventricular, tachycardias), or bradyarrhythmias (e.g., sinus arrest, atrioventricular block, Stokes-Adams attacks). Reflex vasodilation or bradycardia may also result in syncope (vasovagal syncope, carotid sinus syncope, micturition syncope, cough syncope, or neurocardiogenic syncope), as may acute pulmonary embolism and hypovolemia. Because global, or at the very least bilateral, cortical ischemia is required to produce syncope, it rarely occurs as a result of unilateral carotid artery disease. However, syncope is occasionally the result of bilateral carotid artery disease and can also occur when disease of the vertebrobasilar system results in brainstem ischemia. In up to 50% of patients, the cause of a syncopal episode cannot be determined; however, in the cases in which a cause is determined, the most important factor in establishing the diagnosis is obtaining an accurate history of the event. Edema is a nonspecific symptom that commonly accompanies cardiac disease as well as renal disease (e.g., nephrotic syndrome), hepatic disease (e.g., cirrhosis), and local venous abnormalities (e.g., thrombophlebitis, chronic venous stasis). When edema occurs as a result of cardiac disease, it reflects an increase in venous pressure. This increased pressure alters the balance between the venous hydrostatic and oncotic forces, resulting in extravasation of fluid into the extravascular space. When this process occurs as a result of elevated left-sided heart pressure, pulmonary edema results, whereas elevated right-sided heart pressure results in peripheral edema. Characteristically, the peripheral edema of heart failure is pitting; that is, an indentation is left in the skin after pressure is applied to the edematous region. The edema is exacerbated by long periods of standing, is worse in the evening, improves after lying down, and may first be noted when a patient has difficulty in fitting into his or her shoes. The edema may shift to the sacral region after a patient lies down for several hours. When visible edema is noted, it is usually preceded by a moderate weight gain (i.e., 5 to 10 lb), indicative of volume retention. As heart failure progresses, the edema may extend to the thighs and involve the genitalia and abdominal wall, and fluid may collect in the abdominal (ascites) or thoracic (pleural effusion) cavities. Anasarca with ascites should raise suspicion for constrictive peri carditis because this disease may progress very slowly and insidiously. Cyanosis is an abnormal bluish discoloration of the skin resulting from an increase in the level of reduced hemoglobin in the blood and, in general, reflects an arterial oxygen saturation of 85% or less (normal arterial oxygen saturation, ≥95%). Central cyanosis exhibits as cyanosis of the lips or trunk and often reflects right-to-left shunting of blood caused by structural cardiac abnormalities (e.g., atrial or ventricular septal defects) or pulmonary parenchymal or vascular disease (e.g., chronic obstructive pulmonary disease, pulmonary embolism, pulmonary arteriovenous fistula). Peripheral cyanosis may occur because of systemic vasoconstriction in the setting of poor cardiac output or may be a localized phenomenon resulting from venous or arterial occlusive or vasospastic disease (e.g., venous or arterial thrombosis, arterial embolic disease, Raynaud disease). When cyanosis occurs in childhood, it usually reflects congenital heart disease with right-to-left shunting of blood.

35

Myriad other symptoms, many of them nonspecific, may occur with cardiac disease. Fatigue frequently occurs in the setting of poor cardiac output or may occur secondary to the medical therapy of cardiac disease from overdiuresis, aggressive blood pressure lowering, or use of β-blocking agents. Nausea and vomiting frequently occur during an acute myocardial infarction and may also reflect intestinal edema in the setting of right ventricular heart failure. Anorexia and cachexia may occur in severe heart failure. Positional fluid shifts may result in polyuria and nocturia in patients with edema. In addition, epistaxis, hoarseness, hiccups, fever, and chills may reflect underlying cardiovascular disease. Many patients with significant cardiac disease are asymptomatic. Patients with coronary artery disease frequently have periods of asymptomatic ischemia that can be documented with ambulatory electrocardiographic monitoring. Furthermore, nearly one third of patients who suffer an acute myocardial infarction are unaware of the event. This silent ischemia appears to be more common in older adults and in patients with diabetes. Patients may also be asymptomatic despite having severely depressed ventricular function; this usually bespeaks a chronic, slowly progressive process. Reduced exercise capacity may only be seen during provocative testing. Similarly, recent findings show that a high percentage of episodes of atrial fibrillation are unrecognized by patients.

Assessment of Functional Capacity In patients with cardiac disorders, the ability or inability to perform various activities (functional status) plays an important role in determining their extent of disability, deciding when to institute various therapies or interventions, and assessing their response to therapy as well as determining their overall prognosis. The New York Heart Association Functional Classification is a standardized method for the assessment of functional status (Table 4-3) and relates functional capacity to the presence or absence of cardiac symptoms during the performance of usual activities. The

Table 4-3 Classification of Functional Status Class I

Uncompromised

Class II

Slightly compromised

Class III

Moderately compromised

Class IV

Severely compromised

Ordinary activity does not cause symptoms.* Symptoms only occur with strenuous or prolonged activity. Ordinary physical activity results in symptoms; no symptoms at rest. Less than ordinary activity results in symptoms; no symptoms at rest. Any activity results in symptoms; symptoms may be present at rest.

*Symptoms refer to undue fatigue, dyspnea, palpitations, or angina in the New York Heart Association classification and refer specifically to angina in the Canadian Cardiovascular Society classification.

36


Physical Examination

merge with the c wave (c-v wave), thus diminishing or eliminating the x descent altogether. The y descent is attenuated in tricuspid stenosis, owing to the impaired atrial emptying. In pericardial constriction and restrictive cardiomyopathy, as well as in right ventricular infarction, the y descent becomes rapid and deep, and the x descent may also become prominent (w waveform). In pericardial tamponade, the x descent is prominent, but the y descent is diminished or absent.

EXAMINATION OF THE JUGULAR VENOUS PULSATIONS

EXAMINATION OF THE ARTERIAL PULSE

The examination of the neck veins allows for estimation of the right atrial pressure and for identification of the venous waveforms. The right internal jugular vein is used for this examination because it more accurately reflects right atrial pressure than the external jugular or left jugular vein. With the patient lying at a 45-degree angle (higher in patients with elevated venous pressure, lower in patients with low venous pressure) with the head turned to the left, the vertical distance from the sternal angle (angle of Louis) to the top of the venous pulsation can be determined. Because the right atrium lies about 5 cm vertically below the sternal angle, distention of the internal jugular vein 4 cm above the sternal angle reflects a right atrial pressure of 9 cm H2O. The right atrial pressure is normally 5 to 9 cm H2O and is increased with congestive heart failure, tricuspid insufficiency or stenosis, and restrictive or constrictive heart disease. With inspiration, negative intrathoracic pressure develops, venous blood drains into the thorax, and the normal venous pressure falls; the opposite is true with expiration. This pattern is reversed (Kussmaul sign) in the setting of right ventricular heart failure, constrictive pericarditis, or restrictive myocardial disease. With right ventricular heart failure, the elevated venous pressure results in passive congestion of the liver. Pressure applied over the liver for 1 to 3 minutes in this setting results in an increase in the jugular venous pressure (hepatojugular reflux). The normal waveforms of the venous pulsation consist of the a, c, and v waves and the x and y descents; these waveforms are shown in Figure 4-1A and reflect events in the right side of the heart. The a wave results from atrial contraction. Subsequent atrial relaxation results in a decrease in the right atrial pressure, which is seen as the x descent. This descent is interrupted by the c wave, generated by the bulging of the tricuspid valve cusps into the right atrium during ventricular systole. As the atrial pressure increases owing to venous return, the v wave is generated. This wave is normally smaller than the a wave and is followed by the y descent as the tricuspid valve opens and blood flows from the right atrium to the right ventricle during diastole. Abnormalities of the venous waveforms reflect underlying structural, functional, or electrical abnormalities of the heart (see Fig. 4-1B through G). The a wave increases in any condition in which greater resistance to right atrial emptying occurs (e.g., tricuspid stenosis, right ventricular hypertrophy or failure, pulmonary hypertension). Cannon a waves are seen when the atrium contracts against a closed tricuspid valve, as occurs with complete heart block, with junctional or ventricular rhythms, and occasionally with ventricular pacemakers. The a wave is absent in atrial fibrillation. In tricuspid regurgitation, the v wave is prominent and may

The arterial blood pressure can be measured with the use of a sphygmomanometer. The cuff is applied to the upper arm, rapidly inflated to 30 mm Hg above the anticipated systolic pressure, and then slowly deflated (= 3 mm Hg/sec) while listening for the sounds produced by blood entering the previously occluded brachial artery (Korotkoff sounds). The pressure at which the first sound is heard (usually a clear, tapping sound) represents the systolic pressure. Diastolic pressure occurs at the point at which the Korotkoff sounds disappear. Normally, the pressure in both arms is the same (about 120/70 mm Hg), and the systolic pressure in the legs is 10 to 20 mm Hg higher. Asymmetrical arm pressures can result from atherosclerotic disease of the aorta, aortic dissection, and stenosis of the innominate or subclavian arteries. Coarctation of the aorta and severe atherosclerotic disease of the aorta or the femoral or iliac arteries can result in a lower blood pressure in the legs than in the arms. Aortic insufficiency is frequently associated with a leg pressure more than 20 mm Hg higher than the arm pressure (Hill sign). Use of a cuff that is too small for a patient’s arm will result in erroneously high pressure measurements. Similarly, a cuff that is too large results in erroneously low measurements. The arterial examination should include assessments of the carotid, radial, brachial, femoral, popliteal, posterior tibial, and dorsalis pedis pulses, although the carotid artery pulse most accurately reflects the central aortic pulse. The rhythm, strength, contour, and symmetry of the pulses should be noted. The normal arterial pulse (Fig. 4-2A) rises rapidly to a peak in early systole, plateaus, and then falls. The descending pressure wave is interrupted by the dicrotic notch, related to aortic valve closure. This normal pattern is altered in a variety of cardiovascular disease states (see Fig. 4-2B through F). The amplitude of the pulse increases in aortic insufficiency, anemia, pregnancy, and thyrotoxicosis and decreases in conditions such as hypovolemia, tachycardia, left ventricular failure, and severe mitral stenosis. Aortic insufficiency results in a bounding pulse (Corrigan pulse or water-hammer pulse), owing to an increased pulse pressure (the difference between systolic and diastolic pressure), and is accompanied by a multitude of abnormalities in the peripheral pulses that reflect this increased pulse pressure. Aortic stenosis characteristically results in an attenuated carotid pulse with a delayed upstroke (pulsus parvus et tardus) and may be associated with a palpable thrill over the aortic area (the carotid shudder). A bisferious pulse is commonly felt in the presence of pure aortic regurgitation and is characterized by two systolic peaks. The first peak is the percussion wave, resulting from the rapid ejection of a large volume of blood early in systole; the second peak is the tidal

Canadian Cardiovascular Society has provided a similar classification of functional status specifically in patients with angina pectoris. These tools are useful in that they allow a patient’s symptoms to be classified and then compared with their symptoms at a different point in time.


37

QRS T

P

ECG S1

S4

S2

S3

phono

A a

x

v

c

a wave caused by atrial contraction, v wave during ventricular systole

y

x'

v c

B

Atrial fibrillation, no a wave present

a v

Enhanced a wave

C a

c-v Dominant c-v wave

D

x

y

x

y

Exaggerated x and y descents in constrictive pericarditis

E

F

cannon a

cannon a

a

Exaggerated x descent and loss of y descent in tamponade

cannon a

cannon a

a JVP

G P

P

P

P

P

P

P

P

P

ECG P

Figure 4-1 Normal and abnormal jugular venous pulse tracings. A, Normal jugular pulse tracing with simultaneous electrocardiogram (ECG) and phonocardiogram. B, Loss of the a wave in atrial fibrillation. C, Large a wave in tricuspid stenosis. D, Large c-v wave in tricuspid regurgitation. E, Prominent x and y descents in constrictive pericarditis. F, Prominent x descent and diminutive y descent in pericardial tamponade. G, Jugular venous pulse (JVP) tracing and simultaneous ECG during complete heart block demonstrating cannon a waves occurring when the atrium contracts against a closed tricuspid valve during ventricular systole.

wave, a reflected wave from the periphery. This bifid pulse may also be noted in hypertrophic cardiomyopathy in which the initial rapid upstroke of the pulse is cut short by the development of a left ventricular outflow tract obstruction, resulting in a fall in the pulse. The reflected wave again produces the second impulse. In severe left ventricular dysfunc-

tion, the intensity of the pulse may alternate from beat to beat (pulsus alternans), and in atrial fibrillation, the pulse intensity is variable. With inspiration, negative intrathoracic pressure is transmitted to the aorta, and the systolic pressure normally decreases by up to 10 mm Hg. Pulsus paradoxus is an exaggeration of this normal inspiratory fall in systolic

38


A

120 mm Hg

D

80 mm Hg 150 mm Hg

B 30 mm Hg Wide pulse pressure 100 mm Hg

C

80 mm Hg Delayed peak, narrow pulse pressure variable

D

variable

Bi-phase peak

90 mm Hg Alternating higher and lower pressure 60 mm Hg

E

90 mm Hg 70 mm Hg

F

60 mm Hg Expiration

Inspiration

Expiration

Figure 4-2 Normal and abnormal carotid arterial pulse contours. A, Normal arterial pulse with simultaneous electrocardiogram (ECG). The dicrotic wave (D) occurs just after aortic valve closure. B, Wide pulse pressure in aortic insufficiency. C, Pulsus parvus et tardus (small amplitude with a slow upstroke) associated with aortic stenosis. D, Bisferious pulse with two systolic peaks, typical of hypertrophic obstructive cardiomyopathy or aortic insufficiency, especially if concomitant aortic stenosis is present. E, Pulsus alternans, characteristic of severe left ventricular failure. F, Paradoxic pulse (systolic pressure decrease of >10 mm Hg with inspiration), most characteristic of cardiac tamponade.

pressure and is characteristically seen with pericardial tamponade, although it may also occur as a result of severe obstructive lung disease, constrictive pericarditis, hypovolemic shock, and pregnancy. Atherosclerotic disease of the peripheral vascular system frequently accompanies coronary atherosclerosis; therefore, the presence of peripheral vascular disease warrants a search for symptoms or signs of coronary artery disease and vice versa. When atherosclerosis occurs in a peripheral artery to the lower extremity and impairs blood flow distally, the patient may complain of intermittent cramping in the buttocks, thigh, calf, or foot (claudication). Severe peripheral vascular disease may result in digital ischemia or necrosis, without or with associated erectile dysfunction (Leriche syndrome). The peripheral pulses should be palpated and the abdominal aorta assessed for enlargement in all cardiac patients; a pulsatile, expansile, periumbilical mass suggests the presence of an abdominal aortic aneurysm. With significant stenosis of the peripheral vasculature, the distal

pulses may be diminished or absent, and the blood flow through the stenotic artery may be audible (a bruit). With normal aging, the elastic arteries lose their compliance, and this change in physical property may obscure abnormal findings.

EXAMINATION OF THE PRECORDIUM Inspection and palpation of the precordium may yield valuable clues as to the existence of cardiac disease. Chest wall abnormalities should be noted, such as pectus excavatum, which may be associated with Marfan syndrome or mitral valve prolapse; pectus carinatum, which may be associated with Marfan syndrome; and kyphoscoliosis, which is occasionally a cause of secondary pulmonary hypertension and right ventricular heart failure. The presence of visible pulsations in the aortic (second right intercostal space and suprasternal notch), pulmonic (third left intercostal space), right ventricular (left parasternal region), and left ventricu-

Chapter 4—Evaluation of the Patient with Cardiovascular Disease lar (fourth to fifth intercostal space and left mid-clavicular line) regions should be noted and will help direct the palpation of the heart. Retraction of the left parasternal area may be seen with severe left ventricular hypertrophy, and systolic retraction of the chest wall at the cardiac apex or left axilla (Broadbent sign) is characteristic of constrictive pericarditis. Precordial palpation is best performed with the patient supine or in the left lateral position, with the examiner standing to the patient’s right side. In this position, firm placement of the examiner’s right hand over the patient’s lower left chest wall places the fingertips over the region of the cardiac apex and the palm over the region of the right ventricle. The normal cardiac apical impulse is a brief, discrete impulse (about 1 cm) located in the fourth to fifth intercostal space in the left mid-clavicular line generated as the left ventricle strikes the chest wall during early systole. In a patient with a structurally normal heart, the apex is the point of maximal impulse (PMI) of the heart against the chest wall. Enlargement of the left ventricle results in lateral displacement of the apical impulse, whereas chronic obstructive pulmonary disease may result in inferior displacement of the PMI. Volume overload states, such as aortic insufficiency and mitral regurgitation, produce ventricular enlargement primarily from dilation and result in a hyperdynamic apical impulse; that is, the impulse is brisk and increased in amplitude. Pressure overload states, such as aortic stenosis and long-standing hypertension, produce ventricular enlargement primarily from hypertrophy. In this setting, the apical impulse is sustained, and atrial contraction is frequently detected (a palpable S4). Hypertrophic cardiomyopathy characteristically produces a double or triple apical impulse. Left ventricular aneurysms produce an apical impulse that is larger than normal and dyskinetic. The right ventricular impulse is not normally palpable. When an impulse is felt over the left parasternal region, it usually reflects right ventricular hypertrophy or dilation. Aortic aneurysms may be palpable (or visible) in the suprasternal notch or the second right intercostal space. Pulmonary hypertension may produce a palpable systolic impulse in the left third intercostal space and may also be associated with a palpable pulmonic component of the second heart sound (P2). Harsh murmurs originating from valvular or congenital heart disease may be associated with palpable vibratory sensations (thrills), as can occur with aortic stenosis, hypertrophic cardiomyopathy, and ventricular septal defects.

Auscultation TECHNIQUE Auscultation of the heart should ideally be performed in a quiet room with the patient in a comfortable position and the chest fully exposed. Certain heart sounds are better heard with either the bell or diaphragm of the stethoscope. Lowfrequency sounds are best heard with the bell applied to the chest wall with just enough pressure to form a seal. As more pressure is applied to the bell, low-frequency sounds are filtered out. High-frequency sounds are best heard with the diaphragm firmly applied to the chest wall. In a patient

39

with a normally situated heart, four major zones of cardiac auscultation are assessed. Aortic valvular events are best heard in the second right intercostal space. Pulmonary valvular events are best heard in the second left interspace. The fourth left interspace is ideal for auscultating tricuspid valvular events, and mitral valvular events are best heard at the cardiac apex or PMI. Because anatomic abnormalities, both congenital and acquired, can alter the location of the heart in the chest, the auscultatory areas may vary among patients. For instance, in patients with emphysema, the heart is shifted downward, and heart sounds may be best heard in the epigastrium. In dextrocardia, the heart lies in the right hemithorax, and the auscultatory regions are reversed. Additionally, auscultation in the axilla or supraclavicular areas or over the thoracic spine may be helpful in some settings, and having the patient lean forward, exhale, or perform various maneuvers may help accentuate particular heart sounds (Table 4-4).

NORMAL HEART SOUNDS The two major heart sounds heard during auscultation are termed S1 and S2. These heart sounds are high-pitched sounds originating from valve closure (Web Sounds, normal). S1 occurs at the onset of ventricular systole and corresponds to closure of the atrioventricular valves. It is usually perceived as a single sound, although occasionally its two components, M1 and T1, corresponding to closure of the mitral and tricuspid valves, respectively, can be heard. M1 occurs earlier, is the louder of the two components, and is best heard at the cardiac apex. T1 is somewhat softer and heard at the left lower sternal border. The second heart sound results from closure of the semilunar valves. The two components, A2 and P2, originating from aortic and pulmonic valve closure, respectively, can be easily distinguished. A2 is usually louder than P2 and is best heard at the right upper sternal border. P2 is loudest over the second left intercostal space. During expiration, the normal S2 is perceived as a single event. However, during inspiration, the augmented venous return to the right side of the heart and the increased capacitance of the pulmonary vascular bed result in a delay in pulmonic valve closure. In addition, the slightly decreased venous return to the left ventricle results in slightly earlier aortic valve closure. Thus, physiologic splitting of the second heart sound, with A2 preceding P2 during inspiration, is a normal respiratory event. Occasionally, additional heart sounds may be heard in normal individuals. A third heart sound (see later discussion) can be heard in normal children and young adults, in whom it is referred to as a physiologic S3; it is rarely heard after the age of 40 years in healthy individuals (Web Sounds, S3). A fourth heart sound (S4) is generated by forceful atrial contraction and is rarely audible in normal young indi viduals but is fairly common in older individuals (Web Sounds, S4). A murmur is an auditory vibration usually generated either by abnormally increased flow across a normal valve or by normal flow across an abnormal valve or structure. Innocent murmurs are always systolic murmurs, are usually soft and brief, and are by definition not associated with abnormalities of the cardiovascular system. They arise from

40


Table 4-4 Effects of Physiologic Maneuvers on Auscultatory Events Maneuver

Major Physiologic Effects

Useful Auscultatory Changes

Respiration

↑ Venous return with inspiration

Valsalva (initial ↑ BP, phase I; followed by ↓ BP, phase II)

↓ BP, ↓ venous return, ↓ LV size (phase II)

Standing

↑ Venous return ↑ LV size

Squatting

↑ ↑ ↑ ↑ ↑

Venous return Systemic vascular resistance LV size Arterial pressure Cardiac output

↑ ↑ ↓ ↑ ↓ ↑ ↑ ↓

Ventricular filling Contractility Arterial pressure Cardiac output LV size Arterial pressure Cardiac output LV size

↑ Right heart murmurs and gallops with inspiration; splitting of S2 (see Fig. 4-3) ↑ HCM ↓ AS, MR MVP click earlier in systole; murmur prolongs ↑ HCM ↓ AS, MR MVP click earlier in systole; murmur prolongs ↑ AS, MR, AI ↓ HCM MVP click delayed; murmur shortens ↑ Gallops ↑ MR, AI, MS ↓ AS, HCM ↑ AS Little change in MR ↑ HCM, AS, MS ↓ AI, MR, Austin Flint murmur MVP click earlier in systole; murmur prolongs ↑ MR, AI ↓ AS, HCM MVP click delayed; murmur shortens

Isometric exercise (e.g., handgrip)

Post PVC or prolonged R-R interval Amyl nitrate

Phenylephrine

↑, Increased intensity; ↓, decreased intensity; AI, aortic insufficiency; AS, aortic stenosis; BP, blood pressure; HCM, hypertrophic cardiomyopathy; LV, left ventricle; MR, mitral regurgitation; MS, mitral stenosis; MVP, mitral valve prolapse; PVC, premature ventricular contraction; R-R, interval between the R waves on an electrocardiogram.

flow across the normal aortic or pulmonic outflow tracts and are present in a large proportion of children and young adults. Murmurs associated with high-flow states (e.g., pregnancy, anemia, fever, thyrotoxicosis, exercise) are not considered innocent, although they are not usually associated with structural heart disease. These are termed physiologic murmurs, owing to their association with altered physiologic states. Diastolic murmurs are never innocent or physiologic.

ABNORMAL HEART SOUNDS Abnormalities of S1 and S2 relate to abnormalities in their intensity (Table 4-5) or abnormalities in their respiratory splitting (Table 4-6). As noted, splitting of the S1 is normal but not frequently noted. This splitting becomes more apparent with right bundle branch block or with Ebstein anomaly of the tricuspid valve, owing to delay in closure of the tricuspid valve in these conditions (Web Sounds, Ebstein). The intensity of S1 is determined in part by the opening state of the atrioventricular valves at the onset of ventricular systole. If the valves are still widely open, as may occur with tachycardia or a short P-R interval, S1 will be accentuated. Conversely, in the presence of a long P-R interval, the mitral valve drifts toward a closed position before the onset of ventricular systole, and the subsequent S1 is soft. The intensity of S1 may vary in the presence of Mobitz type I heart block, atrioventricular dissociation, and atrial fibrillation when the relationship between atrial and ventricular systole varies. In mitral

stenosis with a pliable valve, the persistent pressure gradient at the end of diastole keeps the mitral valve leaflets relatively open and results in a loud S1 at the onset of systole. In severe mitral stenosis, when the mitral valve is heavily calcified and has decreased leaflet excursion, S1 becomes faint or absent (Figs. 4-3 and 4-4). S2 may be loud in systemic hypertension, owing to accentuated aortic valve closure (loud A2), or in pulmonary hypertension, owing to accentuated pulmonic valve closure (loud P2). When the aortic or pulmonary valves are stenotic, the force of valve closure is decreased, thus A1 and P2 become soft or inaudible. In this setting, S2 may appear to be single; in the setting of aortic stenosis, prolonged left ventricular ejection narrows the normal splitting of S2; and with severe aortic stenosis, S2 may become absent altogether as prolonged ejection and its accompanying murmur obscure P2. Wide splitting of the S2 with normal respiratory variation occurs when either pulmonic valve closure is delayed (e.g., right bundle branch block, pulmonic stenosis) or aortic valve closure occurs earlier owing to more rapid ejection of left ventricular volume (e.g., mitral regurgitation, ventricular septal defect). Fixed splitting of S2 without respiratory variation is characteristic of atrial septal defects and also occurs with right ventricular failure (Web Sounds, ASD). Paradoxic splitting of S2 is a reversal of the usual closure sequence of the aortic and pulmonic valves (i.e., P2 precedes A2). In this setting, a single S2 with inspiration and splitting of S2 with expiration can be heard. This circumstance occurs most commonly when delay occurs in closure of the aortic valve resulting from either delay in electrical conduction to


41

Table 4-5 Abnormal Intensity of Heart Sounds S1

A2

P2

Loud

Short PR interval Mitral stenosis with pliable valve

Pulmonary hypertension Thin chest wall

Soft

Long PR interval Mitral regurgitation Poor left ventricular function Mitral stenosis with rigid valve Thick chest wall Atrial fibrillation Heart block

Systemic hypertension Aortic dilation Coarctation of the aorta Calcific aortic stenosis Aortic regurgitation

—

—

Varying

Valvular or subvalvular pulmonic stenosis

Table 4-6 Abnormal Splitting of S2 Single S2

Widely Split S2 with Normal Respiratory Variation

— Pulmonic stenosis

Right bundle branch block Left ventricular pacing

Systemic hypertension Coronary artery disease Any condition that can lead to paradoxical splitting of S2

Pulmonic stenosis Pulmonary embolism Idiopathic dilation of the pulmonary artery

Fixed Split S2

Paradoxically Split S2

Atrial septal defect Severe right ventricular dysfunction — — —

Left bundle branch block Right ventricular pacing Angina, myocardial infarction Aortic stenosis Hypertrophic cardiomyopathy Aortic regurgitation

Mitral regurgitation Ventricular septal defect

the left ventricle (e.g., left bundle branch block) or prolonged mechanical contraction of the left ventricle (e.g., aortic stenosis, hypertrophic cardiomyopathy). The third heart sound, S3 (also called the ventricular diastolic gallop), is a low-pitched sound occurring shortly after A2 in mid-diastole and heard best at the cardiac apex with the patient in the left lateral position. A pathologic S3 is distinguished from a physiologic S3 by age or the presence of underlying cardiac disease. It is frequently heard with ventricular systolic dysfunction from any cause and likely results either from blood entering the ventricle during the rapid filling phase of diastole or from the impact of the ventricle against the chest wall. Maneuvers that increase venous return accentuate S3, and maneuvers that decrease venous return make the S3 softer. An S3 can also be heard in hyperdynamic states, where it likely results from rapid early diastolic filling. The left ventricular S3 is best noticed at the cardiac apex, whereas the right ventricular S3 is heard best at the left lower sternal border and increases in intensity with inspiration. The timing of the S3 is similar to the sound generated by atrial tumors (tumor plop) and constrictive pericarditis (pericardial knock) and can also be confused with the opening snap of a stenotic mitral valve. The fourth heart sound, S4 (also called the atrial diastolic gallop), is best heard at the cardiac apex with the bell of the stethoscope. It is a low-pitched sound originating from the active ejection of blood from the atrium into a noncompliant ventricle and is therefore not present in the setting of atrial fibrillation. S4 is commonly heard in patients

with left ventricular hypertrophy from any cause (e.g., hypertension, aortic stenosis, hypertrophic cardiomyopathy) or acute myocardial ischemia and in hyperkinetic states. Frequently, the S4 is also palpable at the cardiac apex. S3 and S4 are occasionally present in the same patient. In the presence of tachycardia or a prolonged PR interval, the S3 and S4 may merge to produce a summation gallop. The opening of normal cardiac valves is not audible. However, abnormal valves may produce opening sounds. In the presence of a bicuspid aortic valve or in aortic stenosis with pliable valve leaflets, an ejection sound is audible as the leaflets open to their maximal extent. A similar ejection sound may originate from a stenotic pulmonic valve, and in this case, the ejection sound decreases in intensity with inspiration. These ejection sounds are high pitched, occur early in systole, and are frequently followed by the typical ejection murmur of aortic or pulmonic stenosis. Ejection sounds are also heard with systemic or pulmonary hypertension, the exact mechanism of which is not clear. Ejection sounds heard in mid to late systole are referred to as systolic clicks and are most commonly associated with mitral valve prolapse. As the redundant mitral valve prolapses and reaches its maximal superior displacement, it produces a high-pitched click. Several clicks may be heard as various parts of the redundant valve prolapse (Web Sounds, MVP). Frequently, the click is followed by a mitral regurgitant murmur. Maneuvers that decrease venous return cause the clicks to occur earlier in systole and the murmur to become longer (see Table 4-4).

42


ECG S1 S2 Loud S1

S2

M1 T1

S1

A2 P2

Loud S2 S1

S2 S3

S4

S3 gallop

S1 S2

S4 S1

S2

S4 gallop S3-4 Summation gallop

S1

S1

S2 Expiration

S2 A P

Physiologic splitting Inspiration

S1

A

P Expiration

S1

A

P Inspiration

S1

A

P

A

P

P

A

S2 OS S3

First Second heart heart sound sound (S1) (S2) Figure 4-4 The relationship of extra heart sounds to the normal first (S1) and second (S2) heart sounds. S1 is composed of the mitral (M1) and tricuspid (T1) closing sounds, although it is frequently perceived as a single sound. S2 is composed of the aortic (A2) and pulmonic (P2) closing sounds, which are usually easily distinguished. A fourth heart sound (S4) is soft and low pitched and precedes S1. A pulmonic or aortic ejection sound (ES) occurs shortly after S1. The systolic click (C) of mitral valve prolapse may be heard in mid or late systole. The opening snap (OS) of mitral stenosis is high pitched and occurs shortly after S2. A tumor plop or pericardial knock occurs at the same time and can be confused with an OS or an S3, which is lower in pitch and occurs slightly later.

Table 4-7 Grading System for Intensity of Murmurs

Fixed splitting

Grade Grade Grade Grade Grade

1 2 3 4 5

Inspiration S1

C

Abnormally wide but physiologic splitting

Expiration S1

S1 ES

Grade 6

Barely audible murmur Murmur of medium intensity Loud murmur, no thrill Loud murmur with thrill Very loud murmur; stethoscope must be on the chest to hear it; may be heard posteriorly Murmur audible with stethoscope off the chest

Expiration S2

Paradoxical splitting

S1 Inspiration

First Second heart heart sound sound Figure 4-3 Abnormal heart sounds can be related to abnormal intensity, abnormal presence of a gallop rhythm, or abnormal splitting of S2 with respiration. ECG, electrocardiogram.

The opening of abnormal mitral or tricuspid valves can also be heard in the presence of rheumatic valvular stenosis, when the sound is referred to as an opening snap (Web Sounds, MS). The snap is heard only if the valve leaflets are pliable and is generated as the leaflets abruptly dome during early diastole. The interval between S2 and the opening snap is of diagnostic importance; as the stenosis worsens and the atrial pressure increases, the mitral valve

opens earlier in diastole, and the interval between the S2 and the opening snap shortens.

MURMURS As stated previously, murmurs are a series of auditory vibrations generated when either abnormal blood flow across a normal cardiac structure or normal flow across an abnormal cardiac structure results in turbulent flow. These sounds are longer than the individual heart sounds and can be described by their location, intensity, frequency (pitch), quality, duration, and timing in relation to systole or diastole. The intensity of a murmur is graded on a scale of 1 to 6 (Table 4-7). In general, murmurs of grade 4 or greater are associated with a palpable thrill. The loudness of a murmur does not necessarily correlate with the severity of the underlying abnormality. For instance, flow across a large atrial septal defect is essentially silent, whereas flow across a small ventricular


Aorta

43

AVO

MVO LA LV

S1 E Systolic ejection murmur Holosystolic regurgitant murmur

S2

OS

S1 E

S1

S2

S1

S1

S2

S1

Diastolic rumbling murmur of mitral stenosis

Decrescendo diastolic murmur

Figure 4-5 Abnormal sounds and murmurs associated with valvular dysfunction displayed simultaneously with left atrial (LA), left ventricular (LV), and aortic pressure tracings. AVO, aortic valve opening; E, ejection click of the aortic valve; MVO, mitral valve opening; OS, opening snap of the mitral valve. The shaded areas represent pressure gradients across the aortic valve during systole or mitral valve during diastole, characteristic of aortic stenosis and mitral stenosis, respectively.

septal defect is frequently associated with a loud murmur (Web Sounds, VSD). Higher-frequency murmurs correlate with a higher velocity of flow at the site of turbulence. Important to note are the pattern or configuration of the murmur (e.g., crescendo, crescendo-decrescendo, decrescendo, plateau) (Fig. 4-5) and the quality of the murmur (e.g., harsh, blowing, rumbling) as well as the location of maximal intensity and the pattern of radiation of the murmur. Various physical maneuvers may help clarify the nature of a particular murmur (see Table 4-4). Murmurs can be divided into three categories—(1) sys tolic, (2) diastolic, and (3) continuous (Table 4-8)—and can result from abnormalities on the right or left side of the heart as well as the great vessels. Right-sided murmurs may become significantly louder after inspiration, owing to the resulting augmentation of venous return, whereas left-sided murmurs are relatively unaffected by respiration. Systolic murmurs can be further divided into ejection-type murmurs and regurgitant murmurs. Ejection murmurs reflect turbulent flow across the aortic or pulmonic valve (Web Sounds, AS and PS). They begin shortly after S1, increase in intensity as the velocity of flow increases, and subsequently decrease in intensity as the velocity falls (crescendo-decrescendo). Examples of ejection-type murmurs include innocent murmurs and the murmurs of aortic sclerosis, aortic stenosis, pulmonic stenosis, and hypertrophic cardiomyopathy. Innocent murmurs and aortic sclerotic murmurs are short in duration and do not radiate (Web Sounds, benign murmur). The duration of aortic or pulmonic stenotic murmurs varies depending on the severity of the stenosis (compare Web Sounds, AS—early and AS—late). With

more severe stenosis, the murmur becomes longer, and the time to peak intensity of the murmur lengthens (i.e., early-, mid-, and late-peaking murmurs). The murmur of aortic stenosis is usually harsh, radiates to the carotid arteries, and at times may radiate to the cardiac apex (Gallavardin phenomenon). The murmur of hypertrophic cardiomyopathy may be confused with aortic stenosis, but it does not radiate to the carotids, and it is the only ejection murmur that becomes louder with decreased venous return. Mitral regurgitation associated with mitral valve prolapse may also show this response, but it is not a typical ejection murmur. The classic regurgitant systolic murmurs of mitral (MR) and tricuspid regurgitation (TR) last throughout all of systole (holosystolic), are plateau in pattern, and terminate at S2 (Web Sounds, MR). With acute MR, the murmur may be limited to early systole and may be somewhat decrescendo in pattern. When MR is secondary to mitral valve prolapse, it starts in mid to late systole and is preceded by a mitral valve click. Ventricular septal defects may also result in holosystolic murmurs, although a small muscular ventricular septal defect may have a murmur limited to early systole. Early-diastolic murmurs result from aortic or pulmonic insufficiency and are decrescendo in pattern. The duration of the murmur reflects chronicity: a short murmur is heard in acute aortic insufficiency or mild insufficiency, whereas chronic aortic insufficiency may produce a murmur throughout diastole. A Graham Steell murmur denotes a pulmonic insufficiency murmur in the setting of pulmonary hypertension. Mid-diastolic murmurs classically result from mitral or tricuspid stenosis, are low pitched, and are referred to as

44


Table 4-8 Classification of Heart Murmurs Timing

Class

Description

Characteristic Lesions

Systolic

Ejection

Begins in early systole; may extend to mid or late systole Crescendo-decrescendo pattern Often harsh in quality Begins after S1 and ends before S2

Holosystolic

Extends throughout systole* Relatively uniform in intensity

Late

Variable onset and duration, often preceded by a nonejection click Begins with A2 or P2 Decrescendo pattern with variable duration Often high pitched, blowing Begins after S2, often after an opening snap Low-pitched rumble heard best with bell of stethoscope

Valvular, supravalvular, and subvalvular aortic stenoses Hypertrophic cardiomyopathy Pulmonic stenosis Aortic or pulmonary artery dilation Malformed but nonobstructive aortic valve ↑ Transvalvular flow (e.g., aortic regurgitation, hyperkinetic states, atrial septal defect, physiologic flow murmur) Mitral regurgitation Tricuspid regurgitation Ventricular septal defect Mitral valve prolapse

Diastolic

Early

Mid

Late Continuous

—

Louder with exercise and left lateral position Loudest in early diastole Presystolic accentuation of mid-diastolic murmur Systolic and diastolic components “machinery murmurs”

Aortic regurgitation Pulmonic regurgitation

Mitral stenosis Tricuspid stenosis ↑ Flow across atrioventricular valves (e.g., mitral regurgitation, tricuspid regurgitation, atrial septal defect) Mitral stenosis Tricuspid stenosis Patent ductus arteriosus Coronary atrioventricular fistula Ruptured sinus of Valsalva aneurysm into right atrium or ventricle Mammary souffle Venous hum

*Encompasses both the first and second heart sounds.

diastolic rumbles. Similar murmurs may be heard with obstructing atrial myxomas or in the presence of augmented diastolic flow across an unobstructed mitral or tricuspid valve, as occurs with an atrial or ventricular septal defect or with significant MR or TR. Severe, chronic aortic insufficiency may also produce a diastolic rumble, owing to premature closure of the mitral valve (Austin Flint murmur). Late-diastolic murmurs reflect presystolic accentuation of the mid-diastolic murmurs, owing to augmented mitral or tricuspid flow after atrial contraction. Continuous murmurs are murmurs that last throughout all of systole and continue into at least early diastole. These murmurs are referred to as machinery murmurs and are generated by continuous flow from a vessel or chamber with high pressure into a vessel or chamber with low pressure. A patent ductus arteriosus produces the classic continuous murmur (Web Sounds, PDA).

sternal border with the patient leaning forward and holding his or her breath at end expiration. The classic rub has three components corresponding to atrial systole, ventricular systole, and ventricular diastole, although frequently only one or two of the components are audible (Web Sounds, pericardial rubs). Localized irritation of the surrounding pleura may result in an associated pleural friction rub (pleuropericardial rub), which varies with respiration. Continuous venous murmurs, or venous hums, are almost universally present in children. They are also frequent in adults, especially during pregnancy or in the setting of thyrotoxicosis or anemia. These murmurs are best heard at the base of the neck with the patient’s head turned to the opposite direction and can be eliminated by gentle pressure over the vein.

OTHER CARDIAC SOUNDS

Prosthetic valves produce characteristic auscultatory findings. Porcine or bovine bioprosthetic valves produce heart sounds that are similar to native valve sounds; however, because these valves are smaller than the native valves that

Pericardial rubs occur in the setting of pericarditis. These rubs produce coarse, scratching sounds heard best at the left

PROSTHETIC HEART SOUNDS

Chapter 4—Evaluation of the Patient with Cardiovascular Disease they replace, they almost always have an associated murmur (systolic ejection murmur when placed in the aortic position and diastolic rumble when placed in the mitral position). Mechanical valves result in crisp, high-pitched sounds related to valvular opening and closure. With ball-in-cage valves (e.g., Starr-Edwards valves, the opening sound is louder than the closure sound. With all other mechanical

45

valves (e.g., Björk-Shiley valves, St. Jude valves), the closure sound is louder. These valves also produce an ejection-type murmur. Listening for all of the expected prosthetic sounds in patients with prosthetic valves is important because dysfunction of these valves may first be suggested by a change in the intensity or quality of the heart sounds or the development of a new or changing murmur.

Prospectus for the Future Thanks to advances in chip technology, the essential art of cardiac auscultation is making a resurgence with the use of the computerized heart sound phonocardiography or acoustic cardiography. Students and experienced practitioners alike will be able to use an algorithm for predicting left ventricular dysfunction based on the characteristics of the S3 and S4 heart sounds

References Pickering TG, Hall JE, Appel LJ, et al: Recommendations for blood pressure measurement in humans and experimental animals. Part 1: Blood pressure measurement in humans: A statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation 111:697-716, 2005.

and biomarkers of disease compensation and progression. Personal digital assistants, smartphones, and other technologies will make inroads for more accurate diagnosis during initial screening evaluation and bedside management of patients with cardiovascular disease.

Goldman L, Ausiello D: Cecil Textbook of Medicine, 22nd ed. Part VIII: Cardiovascular Disease. Philadelphia, WB Saunders, 2004.

III

Chapter

5

Diagnostic Tests and Procedures in the Patient with Cardiovascular Disease Sheldon E. Litwin

Chest Radiography The chest radiograph is an integral part of the cardiac evaluation and gives valuable information regarding structure and function of the heart, lungs, and great vessels. A routine examination includes posteroanterior and lateral projections (Fig. 5-1). In the posteroanterior view, cardiac enlargement may be present when the transverse diameter of the cardiac silhouette is greater than one half the transverse diameter of the thorax. The heart may appear falsely enlarged when it is displaced horizontally, such as with poor inflation of the lungs, and if the film is an anteroposterior projection, which magnifies the heart shadow. Left atrial enlargement is suggested when the left-sided heart border is straightened or bulges toward the left. In addition, the main bronchi may be widely splayed, and a circular opacity or double density within the cardiac silhouette may be seen. Right atrial enlargement may be present when the right-sided heart border bulges toward the right. Left ventricular enlargement results in downward and lateral displacement of the apex. A rounding of the displaced apex suggests ventricular hypertrophy. Right ventricular enlargement is best assessed in the lateral view and may be present when the right ventricular border occupies more than one third of the retrosternal space between the diaphragm and thoracic apex. The aortic arch and thoracic aorta may become dilated and tortuous in patients with severe atherosclerosis, longstanding hypertension, and aortic dissection. Dilation of the proximal pulmonary arteries may occur when pulmonary pressures are elevated and pulmonary vascular resistance is increased. Disease states associated with increased pulmonary artery flow and normal vascular resistance, such as 46

atrial or ventricular septal defects, may result in dilation of the proximal and distal pulmonary arteries. Pulmonary venous congestion secondary to elevated left ventricular heart pressures results in redistribution of blood flow in the lungs and prominence of the apical vessels. Transudation of fluid into the interstitial space may result in fluid in the fissures and along the horizontal periphery of the lower lung fields (Kerley B lines). As venous pressures further increase, fluid collects within the alveolar space, which early on collects preferentially in the inner two thirds of the lung fields, resulting in a characteristic butterfly appearance. Fluoroscopy or plain films may identify abnormal calcification involving the pericardium, coronary arteries, aorta, and valves. In addition, fluoroscopy can be instrumental in evaluating the function of mechanical prosthetic valves. Specific radiographic signs of congenital and valvular diseases are discussed in their respective sections.

Electrocardiography The electrocardiogram (ECG) represents the electrical activity of the heart recorded by skin electrodes. This wave of electrical activity is represented as a sequence of deflections on the ECG (Fig. 5-2). The horizontal scale represents time such that, at a standard paper speed of 25 mm/second, each small box (1 mm) represents 0.04 second, and each large box (5 mm) represents 0.20 second. The vertical scale represents amplitude (10 mm = 1 mV). The heart rate can be estimated by dividing the number of large boxes between complexes (R-R interval) into 300. In the normal heart, the electrical impulse originates in the sinoatrial (SA) node and is conducted through the atria.

Chapter 5—Diagnostic Tests and Procedures in the Patient with Cardiovascular Disease

47

Figure 5-1 Schematic illustration of the parts of the heart, whose outlines can be identified on a routine chest radiograph. A, Posteroanterior chest radiograph. B, Lateral chest radiograph. Ao, aorta; LA, left atrium; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle.

0.2 sec 0.04 sec

1 mv

R

T P

PR interval

ST Q S segment QT interval

Figure 5-2 Normal electrocardiographic complex with labeling of waves and intervals.

Given that depolarization of the SA node is too weak to be detected on the surface ECG, the first, low-amplitude deflection on the surface ECG reflects atrial activation and is termed the P wave. The interval between the onset of the P wave and the next rapid deflection (QRS complex) is known as the PR interval and primarily represents the time taken for the impulse to travel through the atrioventricular (AV) node. The normal PR segment ranges from 0.12 to 0.20 second. A PR interval greater than 0.20 second defines AV nodal block. After the wave of depolarization has moved through the AV node, the ventricular myocardium is depolarized in a sequence of four phases. First, the interventricular septum depolarizes from left to right. This phase is followed by

depolarization of the right ventricle and inferior wall of the left ventricle, then the apex and central portions of the left ventricle, and, finally, the base and the posterior wall of the left ventricle. Ventricular depolarization results in a highamplitude complex on the surface ECG known as the QRS complex. The first downward deflection of this complex is the Q wave, the first upward deflection is the R wave, and the subsequent downward deflection is the S wave. In some individuals, a second upward deflection may be present after the S wave and is termed R prime (R′). Normal duration of the QRS complex is less than 0.10 second. Complexes greater than 0.12 second are usually secondary to some form of interventricular conduction delay. The isoelectric segment after the QRS complex is the ST segment and represents a brief period during which relatively little electrical activity occurs in the heart. The junction between the end of the QRS complex and the beginning of the ST segment is the J point. The upward deflection after the ST segment is the T wave and represents ventricular repolarization. The QT interval, which reflects the duration and transmural gradient of ventricular depolarization and repolarization, is measured from the onset of the QRS complex to the end of the T wave. The QT interval varies with heart rate, but for rates between 60 and 100 beats/ minute, the normal QT interval ranges from 0.35 to 0.44 second. For heart rates outside this range, the QT interval can be corrected by the following formula: QTc = QT (sec ) R-R interval1 2 (sec ) In some individuals, a U wave (of varying amplitude) may be noted after the T wave, the cause of which is unknown. The standard ECG consists of 12 leads: six limb leads (I, II, III, aVR, aVL, and aVF) and six chest or precordial leads (V1 to V6) (Fig. 5-3). The electrical activity recorded in each

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I

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Figure 5-3 Normal 12-lead electrocardiogram.

Left-axis −90° −120°

dev ia

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lead represents the direction and magnitude (vector) of the electrical force as seen from that particular lead position. Electrical activity directed toward a particular lead is represented as an upward deflection, and an electrical impulse directed away from a particular lead is represented as a downward deflection. Although the overall direction of electrical activity can be determined for any of the waveforms previously described, the mean QRS axis is the most clinically useful and is determined by examining the six limb leads. Figure 5-4 illustrates Einthoven triangle and the polarity of each of the six limb leads of the standard ECG. Skin electrodes are attached to both arms and legs, with the right leg serving as the ground. Leads I, II, and III are bipolar leads and represent electrical activity between two leads: lead I represents electrical activity between the right and left arms (left arm positive), lead II between the right arm and left leg (left leg positive), and lead III between the left arm and left leg (left leg positive). Leads aVR, aVL, and aVF are designated the augmented leads. With these leads, the QRS will be positive or have a predominant upward deflection when the electrical forces are directed toward the right arm for aVR, left arm for aVL, and left leg for aVF. These six leads form a hexaxial frontal plane of 30-degree arc intervals. The normal QRS axis ranges from −30 to +90 degrees. An axis more negative than −30 defines left axis deviation, and an axis greater than +90 defines right axis deviation. In general, a positive QRS complex in leads I and aVF suggests a normal QRS axis between 0 and 90 degrees.

No

is ax

Figure 5-4 Hexaxial reference figure for frontal plane axis determination, indicating values for abnormal left and right QRS axis deviations.


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B Figure 5-5 A, Left ventricular hypertrophy as seen on an electrocardiographic recording. Characteristic findings include increased QRS voltage in precordial leads (deep S in lead V2 and tall R in lead V5) and downsloping ST depression and T-wave inversion in lateral precordial leads (strain pattern) and leftward axis. B, Right ventricular hypertrophy with tall R wave in right precordial leads, downsloping ST depression in precordial leads (RV strain), right axis deviation, and evidence of right atrial enlargement.

The six standard precordial leads (V1 to V6) are attached to the anterior chest wall (Fig. 5-5). Lead placement should be as follows: V1—fourth intercostal space, right sternal border; V2—fourth intercostal space, left sternal border; V3—midway between V2 and V4; V4—fifth intercostal space, left mid-clavicular line; V5—level with V4, left anterior axillary line; V6—level with V4, left mid-axillary line. The chest leads should be placed under the breast. Electrical activity directed toward these leads results in a positive deflection on the ECG tracing. Leads V1 and V2 are closest to the right ventricle and interventricular septum, and leads V5 and V6 are closest to the anterior and anterolateral walls of the left ventricle. Normally, a small R wave occurs in lead V1 reflecting septal depolarization and a deep S wave reflecting predominantly left ventricular activation. From V1 to V6, the R wave becomes larger (and the S

wave smaller) because the predominant forces directed at these leads originate from the left ventricle. The transition from a predominant S wave to a predominant R wave usually occurs between leads V3 and V4. Right-sided chest leads are used to look for evidence of right ventricular infarction. ST-segment elevation in V4R has the best sensitivity and specificity for making this diagnosis. For rightsided leads, standard V1 and V2 are switched, and V3R to V6R are placed mirror image to the standard left-sided chest leads. Some groups have advocated the use of posterior leads to increase the sensitivity for diagnosing lateral and posterior wall infarction or ischemia (areas that are often deemed to be electrically silent on traditional 12-lead ECGs). To do this, six additional leads are placed in the fifth intercostal space continuing posteriorly from the position of V6.

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Abnormal Electrocardiographic Patterns CHAMBER ABNORMALITIES AND VENTRICULAR HYPERTROPHY The P wave is normally upright in leads I, II, and F; inverted in aVR; and biphasic in V1. Left atrial abnormality (defined as enlargement, hypertrophy, or increased wall stress) is characterized by a wide P wave in lead II (0.12 second) and a deeply inverted terminal component in lead V1 (1 mm). Right atrial abnormality is present when the P waves in the limb leads are peaked and 2.5 mm or more in height. Left ventricular hypertrophy may result in increased QRS voltage, slight widening of the QRS complex, late intrinsicoid deflection, left axis deviation, and abnormalities of the ST-T segments (see Fig. 5-5A). Multiple criteria with variable sensitivity and specificity for detecting left ventricular hypertrophy are available. The most frequently used criteria are given in Table 5-1. Right ventricular hypertrophy is characterized by tall R waves in leads V1 through V3; deep S waves in leads I, aVL, V5, and V6; and right axis deviation (see Fig. 5-5B). In patients with chronically elevated pulmonary pressures, such as with chronic lung disease, a combination of ECG abnormalities reflecting a right-sided pathologic condition may be present and include right atrial abnormality, right ventricular hypertrophy, and right axis deviation. In patients with acute pulmonary embolus, ECG changes may suggest right

Table 5-1 Electrocardiographic Manifestations of Atrial Abnormalities and Ventricular Hypertrophy Left Atrial Abnormality P-wave duration ≥ 0.12 second Notched, slurred P wave in leads I and II Biphasic P wave in lead V1 with a wide, deep, negative terminal component Right Atrial Abnormality P-wave duration ≤ 0.11 second Tall, peaked P waves of ≥ 2.5 mm in leads II, III, and aVF Left Ventricular Hypertrophy Voltage criteria R wave in lead aVL ≥ 12 mm R wave in lead I ≥ 15 mm S wave in lead V1 or V2 + R wave in lead V5 or V6 ≥ 35 mm Depressed ST segments with inverted T waves in the lateral leads Left axis deviation QRS duration ≥ 0.09 second Left atrial enlargement Right Ventricular Hypertrophy Tall R waves over right precordium (R : S ratio in lead V1 > 1.0) Right axis deviation Depressed ST segments with inverted T waves in leads V1 to V3 Normal QRS duration (if no right bundle branch block) Right atrial enlargement

ventricular strain and include right axis deviation; incomplete or complete right bundle branch block; S waves in leads I, II, and III; and T-wave inversions in leads V1 through V3.

INTERVENTRICULAR CONDUCTION DELAYS The ventricular conduction system consists of two main branches, the right and left bundles. The left bundle further divides into the anterior and posterior fascicles. Conduction block can occur in either of the major branches or in the fascicles (Table 5-2). Fascicular block results in a change in the sequence of ventricular activation but does not prolong overall conduction time (QRS duration remains < 0.10 second). Left anterior fascicular block is a relatively common ECG abnormality and is sometimes associated with right bundle branch block. This conduction abnormality is present when extreme left axis deviation occurs (more negative than −45 degrees); when the R wave is greater than the Q wave in leads I and aVL; and when the S wave is greater than the R wave in leads II, III, and aVF. Left posterior fascicular block is uncommon but is associated with right axis deviation (>90 degrees); small Q waves in leads II, III, and aVF; and small R waves in leads I and aVL. The ECG findings associated with fascicular blocks can be confused with myocardial infarction (MI). For example, with left anterior fascicular block, the prominent QS deflection in leads V1 and V2 can mimic an anteroseptal MI, and the rS deflection in leads II, III, and aVF can be confused with an inferior MI. Similarly, the rS deflection in leads I and aVL in left posterior fascicular block may be confused with a high lateral infarct. The presence of abnormal ST- and T-wave segments and pathologic Q waves (see

Table 5-2 Electrocardiographic Manifestations of Fascicular and Bundle Branch Blocks Left Anterior Fascicular Block QRS duration ≤ 0.1 second Left axis deviation (more negative than −45 degrees) rS pattern in leads II, III, and aVF qR pattern in leads I and aVL Right Posterior Fascicular Block QRS duration ≤ 0.1 second Right axis deviation (+90 degrees or greater) qR pattern in leads II, III, and aVF rS pattern in leads I and aVL Exclusion of other causes of right axis deviation (chronic obstructive pulmonary disease, right ventricular hypertrophy) Left Bundle Branch Block QRS duration ≥ 0.12 second Broad, slurred, or notched R waves in lateral leads (I, aVL, V5, and V6) QS or rS pattern in anterior precordium leads (V1 and V2) ST-T-wave vectors opposite to terminal QRS vectors Right Bundle Branch Block QRS duration ≥ 0.12 second Large R′ wave in lead V1 (rsR′) Deep terminal S wave in lead V6 Normal septal Q waves Inverted T waves in leads V1 and V2

Chapter 5—Diagnostic Tests and Procedures in the Patient with Cardiovascular Disease “Myocardial Ischemia and Infarction” later) are helpful findings to differentiate MI from a fascicular block. Bundle branch blocks are associated with QRS duration longer than 120 milliseconds. In left bundle branch block, depolarization proceeds down the right bundle, across the interventricular septum from right to left, and then to the left ventricle. Characteristic ECG findings include a wide QRS complex; a broad R wave in leads I, aVL, V5, and V6; a deep QS wave in leads V1 and V2; and ST depression and T-wave inversion opposite the QRS deflection (Fig. 5-6A). Given the abnormal sequence of ventricular activation with left bundle branch block, many ECG abnormalities, such as Q-wave MI and left ventricular hypertrophy, are difficult to evaluate. In some cases, acute MI is still apparent even with LBBB. Left bundle branch block almost always indicates the presence of underlying myocardial disease (most commonly fibrosis due to ischemic injury or hypertrophy). With right bundle branch block, the interventricular septum depolarizes normally from left to right, and therefore the initial QRS deflection remains unchanged. As a result, ECG abnormalities such as Q-wave MI can still be interpreted. After septal activation, the left ventricle depolarizes, A

followed by the right ventricle. The ECG is characterized by a wide QRS complex; a large R′ wave in lead V1 (R-S-R′); and deep S waves in leads I, aVL, and V6, representing delayed right ventricular activation (see Fig. 5-6B). Although right bundle branch block may be associated with underlying cardiac disease, it may also appear as a normal variant or be seen intermittently when heart rate is elevated. In the latter case, it is often referred to as rate-related bundle branch block.

MYOCARDIAL ISCHEMIA AND INFARCTION Myocardial ischemia and MI may be associated with abnormalities of the ST segment, T-wave, and QRS complex. Myocardial ischemia primarily affects repolarization of the myocardium and is often associated with horizontal or down-sloping ST-segment depression and T-wave inversion. These changes may be transient, such as during an anginal episode or an exercise stress test, or may be longlasting in the setting of unstable angina or MI. T-wave inversion without ST-segment depression is a nonspecific finding and must be correlated with the clinical setting. B

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Diagnostic criteria for LBBB QRS duration > 0.125 Broad R wave in I1aVL,V5–V6 Deep as in V1–V2 T-wave inversion in lateral leads

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Diagnostic criteria for RBBB QRS duration > 0.125 R > S in V1 RSR in V1 Deep wide S wave I and V6

Figure 5-6 A, Left bundle branch block (LBBB). B, Right bundle branch block (RBBB). Criteria for bundle branch block are summarized in Table 5-2.

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Section III—Cardiovascular Disease I

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Figure 5-7 A, Evolutionary changes in a posteroinferior myocardial infarction. Control tracing is normal. The tracing recorded 2 hours after onset of chest pain demonstrated development of early Q waves, marked ST-segment elevation, and hyperacute T waves in leads II, III, and aVF. In addition, a larger R wave, ST-segment depression, and negative T waves have developed in leads V1 and V2. These are early changes indicating acute posteroinferior myocardial infarction. The 24-hour tracing demonstrates evolutionary changes. In leads II, III, and aVF, the Q wave is larger, the ST segments have almost returned to baseline, and the T wave has begun to invert. In leads V1 to V2, the duration of the R wave now exceeds 0.04 seconds, the ST segment is depressed, and the T wave is upright. (In this example, ECG changes of true posterior involvement extend past lead V2; ordinarily, only leads V1 and V2 may be involved.) Only minor further changes occur through the 8-day tracing. Finally, 6 months later, the ECG illustrates large Q waves, isoelectric ST segments, and inverted T waves in leads II, III, and aVF and large R waves, isoelectric ST segment, and upright T waves in leads V1 and V2, indicative of an old posteroinferior myocardial infarction. B, Example of an ECG from a patient with an underlying LBBB who experienced an acute anterior myocardial infarction. Characteristic ST segment elevation and hyperacute T-waves are seen in leads V1-V6 and leads I and AVL despite the presence of the LBBB. Note that this is not always the case, as a patient with typical symptoms and a LBBB as well as no definite ischemic ST segment elevations should still be treated as if the individual is having an MI or acute coronary syndrome.

Localized ST-segment elevation suggests more extensive myocardial injury and is often associated with acute MI (see Fig. 5-7). Vasospastic or Prinzmetal angina may be associated with reversible ST-segment elevation without MI. STsegment elevation may occur in other settings not related to acute ischemia or infarction. Persistent, localized STsegment elevation in the same leads as pathologic Q waves is consistent with a ventricular aneurysm. Acute pericarditis is associated with diffuse ST-segment elevation and PR depression. Diffuse J-point elevation in association with upward-coving ST segments is a normal variant common among young men and is often referred to as early repolarization. The presence of a Q wave is one of the diagnostic criteria used to verify MI. Infarcted myocardium is unable to conduct electrical activity, and therefore electrical forces will be directed away from the surface electrode overlying the infarcted region, resulting in a Q wave on the surface ECG. Knowing which region of the myocardium each lead represents enables the examiner to localize the area of infarction (Table 5-3). A pathologic Q wave has a duration of greater than or equal to 0.04 second or a depth one fourth or more the height of the corresponding R wave. Not all MIs result in the formation of Q waves. In addition, small R waves can return many weeks to months after an MI. Abnormal Q waves, or pseudoinfarction, may also be associated with nonischemic cardiac disease, such as ventricular pre-excitation, cardiac amyloidosis, sarcoidosis, idiopathic or hypertrophic cardiomyopathy, myocarditis, and chronic lung disease.

ABNORMALITIES OF THE ST SEGMENT AND T WAVE A number of drugs and metabolic abnormalities may affect the ST segment and T wave (Fig. 5-8). Hypokalemia may result in prominent U waves in the precordial leads and prolongation of the QT interval. Hyperkalemia may result in tall, peaked T waves. Hypocalcemia typically lengthens the QT interval, whereas hypercalcemia shortens it. A commonly used cardiac medication, digoxin, often results in diffuse, scooped ST-segment depression. Minor or nonspecific ST-segment and T-wave abnormalities may be present in many patients and have no definable cause. In these instances, the physician must determine the significance of the abnormalities based on the clinical setting. Several excellent websites containing examples of normal and abnormal ECGs are available.

Long-Term Ambulatory Electrocardiographic Recording Ambulatory ECG (Holter monitoring) is a widely used, noninvasive method to evaluate cardiac arrhythmias and conduction disturbances over an extended period and to detect electrical abnormalities that may be brief or transient. With this approach, ECG data from two to three surface leads are stored on a tape recorder that the patient wears for a minimum of 24 to 48 hours. The recorders have both patient-activated event markers and time markers so that any abnormalities can be correlated with the patient’s symptoms or time of day. These data can then be printed in a standard, real-time ECG format for review. For patients with intermittent or rare symptoms, an event recorder, which can be worn for several weeks, may be helpful in identifying the arrhythmia. The simplest device is a small, hand-held monitor that is applied to the chest wall when symptoms occur. The ECG data are recorded and can be transmitted later by telephone to a monitoring center for analysis. A more sophisticated system uses a wrist recorder that allows continuous-loop storage of 4 to 5 minutes of ECG data from one lead. When the patient activates the system, ECG data preceding the event and for 1 to 2 minutes after the event are recorded and stored for further analysis. With both of these devices, the patient must be physically able to activate the recorder during the episode to store the ECG data. Implantable recording devices (subcutaneous) are sometimes used to diagnose infrequent events.

STRESS TESTING Stress testing is an important noninvasive tool for evaluating patients with known or suggested coronary artery disease (CAD). During exercise, the increased demand for oxygen by the working skeletal muscles is met by increases in heart rate and cardiac output. In patients with significant CAD, the increase in myocardial oxygen demand cannot be met by an increase in coronary blood flow. As a result, myocardial ischemia may occur, resulting in chest pain and characteristic ECG abnormalities. These changes, combined with the hemodynamic response to exercise, can give useful diagnostic and prognostic information in the patient with cardiac abnormalities. The most frequent indications for stress testing include establishing a diagnosis of CAD in patients

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Table 5-3 Electrocardiographic Localization of Myocardial Infarction Leads Depicting Primary Electrocardiographic Changes

Infarct Location Inferior Septal Anterior Anteroseptal Extensive anterior Lateral High lateral Posterior† Right ventricular‡

Likely Vessel* Involved

II, III, aVF V1, V2 V3, V4 V1 to V4 I, aVL, V1 to V6 I, aVL, V5 to V6 I, aVL Prominent R in V1 ST elevation in V1 and, more specifically, V4R in setting of inferior infarction

RCA LAD LAD LAD LAD CIRC CIRC RCA or CIRC RCA

*This is a generalization; variations occur. † Usually in association with inferior or lateral infarction. ‡ Usually in association with inferior infarction. CIRC, circumflex artery; LAD, left anterior descending coronary artery; RCA, right coronary artery.

Normal

Hyperkalemia

Hypokalemia

Hypercalcemia Hypocalcemia Hypothermia

Digitalis

Quinidine Procainamide Disopyramide Phenothiazines Tricyclic antidepressants CNS insult (e.g., intracerebral hemorrhage)

Mild to moderate (K = 5-7 mEq/L): Tall, symmetrically peaked T waves with a narrow base More severe (K = 8-11 mEq/L): QRS widens, PR segment prolongs, P wave disappears; ECG resembles a sine wave in severe cases ST depression T-wave flattening Large positive U wave, QT prolongation due to U wave Shortened QT interval due to a shortened ST segment Prolonged QT interval due to a prolonged ST segment; T-wave duration normal Osborne or J waves: J-point elevation with a characteristic elevation of the early ST segment. Slow rhythm, baseline artifact due to shivering often present. ST depression T-wave flattening or inversion Shortened QT interval, increased Uwave amplitude Prolonged QT interval, mainly due to prolonged T-wave duration with flattening or inversion QRS prolongation Increased U-wave amplitude Diffuse, wide, deeply inverted T waves with prolonged QT

u

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u

Figure 5-8 Metabolic and drug influences on the electrocardiographic recording.

with chest pain, assessing prognosis and functional capacity in patients with chronic stable angina or after an MI, evaluating exercise-induced arrhythmias, and assessing for ischemia after a revascularization procedure. The most common form of stress testing uses continuous ECG monitoring while the patient walks on a treadmill.

With each advancing stage, the speed and incline of the belt increases, thus increasing the amount of work the patient performs. The commonly used Bruce protocol employs 3 minutes of exercise at each stage. The modified Bruce protocol incorporates two beginning stages with slower speeds and lesser inclines than are used in the standard Bruce pro-

Chapter 5—Diagnostic Tests and Procedures in the Patient with Cardiovascular Disease tocol. The modified Bruce or similar protocols are generally used for older, markedly overweight, and unstable or more debilitated patients. Exercise testing may also be performed using a bicycle or arm ergometer. The stress test is generally deemed adequate if the patient achieves 90% of his or her predicted maximal heart rate, which is equal to 220 minus the patient’s age. Indications for stopping the test include fatigue, severe hypertension (>220 mm Hg systolic), worsening angina during exercise, developing marked or widespread ischemic ECG changes, significant arrhythmias, or hypotension. The diagnostic accuracy of stress testing is improved with adjunctive echocardiography or radionuclide imaging. Contraindications to stress testing include unstable angina, acute MI, poorly controlled hypertension (blood pressure >220/110 mm Hg), severe aortic stenosis (valve area < 1.0 cm2), and decompensated congestive heart failure. In the era of reperfusion therapy (thrombolytic and percutaneous interventions), for acute coronary syndromes or acute MI, little role exists for the predischarge submaximal stress test that was commonly used in the past. The diagnostic accuracy of the exercise test is dependent on the pre-test likelihood of CAD in a given patient, the sensitivity and specificity of the test results in that patient population, and the ECG criteria used to define a positive test. Clinical features that are most useful at predicting important angiographic coronary disease before exercise testing include advanced age, male sex, and the presence of typical (vs. atypical) anginal chest pain. The diagnostic accuracy and cost-effectiveness of exercise testing is best in patients with an intermediate risk for CAD (30% to 70%) and when ischemic ECG changes are accompanied by chest pain during exercise. Exercise testing is less cost-effective in diagnosing CAD in a patient with classic symptoms of angina because a positive test will not significantly increase the post-test probability of CAD, and a negative test would likely represent a false-negative result. Nonetheless, prognostic information and objective information about the efficacy of pharmacologic therapy may still be obtained. Similarly, exercise testing in young patients with atypical chest pain may not be diagnostically useful, given that an abnormal test result will likely represent a false-positive test and will not significantly increase the post-test probability of CAD. The normal physiologic response to exercise is an increase in heart rate and systolic and diastolic blood pressures. The ECG will maintain normal T-wave polarity, and the ST segment will remain unchanged or, if depressed, will have a rapid upstroke back to baseline. An ischemic ECG response to exercise is defined as (1) 1.5 mm of up-sloping STsegment depression measured 0.08 second past the J point, (2) at least 1 mm of horizontal ST depression, or (3) 1 mm of down-sloping ST-segment depression measured at the J point. Given the large amount of artifact on the ECG that may occur with exercise, these changes must be present in at least three consecutive depolarizations. Other findings suggestive of more extensive CAD include early onset of ST depression (6 minutes); marked, down-sloping ST depression (>2 mm), especially if present in more than five leads; ST changes persisting into recovery for more than 5 minutes; and failure to increase systolic blood pressure to 120 mm Hg or more or a sustained decrease of 10 mm Hg or more below baseline.

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The ECG is not diagnostically useful in the presence of left ventricular hypertrophy, left bundle branch block, WolffParkinson-White syndrome, or chronic digoxin therapy. In these instances, nuclear or echocardiographic imaging is needed to diagnose ischemia. In patients who are unable to exercise, pharmacologic stress testing with myocardial imaging has been shown to have sensitivity and specificity for detecting CAD equal to those of exercise stress imaging. Intravenous dipyridamole and adenosine and newer selective adenosine A2A receptor agonists are coronary vasodilators that result in increased blood flow in normal arteries without significantly changing flow in diseased vessels. The resulting heterogeneity in blood flow can be detected by nuclear imaging techniques and the regions of myocardium supplied by diseased vessels identified. Another commonly used technique to evaluate for ischemia is dobutamine-stress echocardiography. Dobutamine is an inotropic agent that increases myocardial oxygen demand by increasing heart rate and contractility. The echocardiogram is used to monitor for ischemia, which is defined as new or worsening wall motion abnormalities during the infusion. Demon strating improvement in wall thickening with low-dose dobutamine suggests that there is myocardial viability of abnormal segments (i.e., segments that are hypokinetic or akinetic at baseline).

ECHOCARDIOGRAPHY Echocardiography is a widely used, noninvasive technique in which sound waves are used to image cardiac structures and evaluate blood flow. A piezoelectric crystal housed in a transducer placed on the patient’s chest wall produces ultrasound waves. As the sound waves encounter structures with different acoustic properties, some of the ultrasound waves are reflected back to the transducer and recorded. Ultrasound waves emitted from a single, stationary crystal produce an image of a thin slice of the heart (M mode), which can then be followed through time. Steering the ultrasound beam across a 90-degree arc multiple times per second creates two-dimensional imaging (Fig. 5-9). Transthoracic echocardiography is safe, simple, fast, and relatively inexpensive. Hence it is the most commonly used test to assess cardiac size, structure, and function. The development of three-dimensional echocardiographic imaging techniques offers great promise for more accurate measurements of chamber volumes and mass as well as the assessment of geometrically complex anatomy and valvular lesions (Web Fig. 5-1 shows a three-dimensional image). Doppler echocardiography allows assessment of both direction and velocity of blood flow within the heart and great vessels. When ultrasound waves encounter moving red blood cells, the energy reflected back to the transducer is altered. The magnitude of this change (Doppler shift) is represented as velocity on the echocardiographic display and can be used to determine whether the blood flow is normal or abnormal (Fig. 5-10). In addition, the velocity of a particular jet of blood can be converted to pressure using the modified Bernoulli equation (ΔP ≅ 4v2). This process allows for the assessment of pressure gradients across valves or between chambers. Color Doppler imaging allows visualization of blood flow through the heart by assigning a color to the red blood cells based on their velocity and direction

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RV LV

IVS

Ao

RV

MV

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PW

A

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Figure 5-9 Portions of standard two-dimensional echocardiograms (A, parasternal long-axis view; B, apical four-chamber view) showing the major cardiac structures. Ao, aorta; IVS, interventricular septum; LA, left atrium; LV, left ventricle; MV, mitral valve; PE, pericardial effusion; PW, posterior LV wall; RV, right ventricle. See Web Figure 5-3 for a moving image of a two-dimensional echocardiogram. (Image courtesy of Sheldon E. Litwin, MD, Division of Cardiology, University of Utah.)

Figure 5-10 Doppler tracing in a patient with aortic stenosis and regurgitation. The velocity of systolic flow is related to the severity of obstruction.

(Fig. 5-11; Web Fig. 5-2). By convention, blood moving away from the transducer is represented in shades of blue, and blood moving toward the transducer is represented in red. Color Doppler imaging is particularly useful in identifying valvular insufficiency and abnormal shunt flow between chambers. Recently, the use of Doppler techniques to record myocardial velocities or strain rates has provided new insight into myocardial function and hemodynamics. Two-dimensional echocardiography and Doppler echo cardiography are often used in conjunction with exercise or pharmacologic stress testing. Although variability occurs among studies, the sensitivity of stress echocardiography is apparently slightly lower, but the specificity is slightly

higher, compared with myocardial perfusion imaging with nuclear tracers. The overall cost-effectiveness of stress echocardiography is estimated to be significantly better than nuclear perfusion imaging because of the lower cost. The development of ultrasound contrast agents composed of microbubbles that are small enough to transit through the pulmonary circulation has greatly improved the ability to use ultrasound to image obese patients, patients with lung disease, and those with otherwise difficult acoustic windows (Fig. 5-12; Web Fig. 5-3 shows a dynamic contrast echocardiographic image). These agents are also being developed as molecular imaging agents by complexing the bubbles to

Chapter 5—Diagnostic Tests and Procedures in the Patient with Cardiovascular Disease compounds that can selectively bind to the target site of interest (i.e., clots, neovessels). Transesophageal echocardiography (TEE) allows twodimensional and Doppler imaging of the heart through the esophagus by having the patient swallow a gastroscope mounted with an ultrasound crystal within its tip. Given

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the close proximity of the esophagus to the heart, highresolution images can be obtained, especially of the left atrium, mitral valve apparatus, and aorta. TEE is particularly useful in diagnosing aortic dissection, endocarditis, prosthetic valve dysfunction, and left atrial masses (Fig. 5-13; Web Fig. 5-4).

NUCLEAR CARDIOLOGY Radionuclide imaging of the heart allows quantification of left ventricular size and systolic function as well as myocardial perfusion. With radionuclide ventriculography, the patient’s red blood cells are labeled with a small amount of a radioactive tracer (usually technetium-99m). Left ventricular function can then be assessed by one of two methods. With the first-pass technique, radiation emitted by the tagged red blood cells as they initially flow though the heart is detected by a gamma camera positioned over the patient’s chest. With the gated equilibrium method, or multigated acquisition (MUGA) method, the tracer is allowed to achieve an equilibrium distribution throughout the blood pool before count acquisition begins. This second method improves the resolution of the ventriculogram. For both techniques, the gamma camera can be gated to the ECG, allowing for determination of the total emitted end-diastole counts (EDC) and end-systole counts (ESC). Left ventricular ejection fraction (LVEF) can then be calculated as follows:

LV

LA

Figure 5-11 Color Doppler recording demonstrating severe mitral regurgitation. The regurgitant jet seen in the left atrium (LA) is represented in blue because blood flow is directed away from the transducer. The yellow components are the mosaic pattern traditionally assigned to turbulent or high-velocity flow. The arrow points to the hemisphere of blood accelerating proximal to the regurgitant orifice (proximal isovelocity surface area [PISA]). The size of the PISA can be used to help grade the severity of regurgitation. LA, left atrium; LV, left ventricle. See Web Figure 5-2 for a dynamic echocardiographic image in a patient with mitral regurgitation. (Image courtesy of Sheldon E. Litwin, MD, Division of Cardiology, University of Utah.)

A

LVEF = ( EDC − ESC ) EDC If scintigraphic information is collected throughout the cardiac cycle, a computer-generated image of the heart can be displayed in a cinematic fashion, allowing for the assessment of wall motion. Myocardial perfusion imaging is usually performed in conjunction with exercise or pharmacologic (vasodilator) stress testing. Persantine, or more commonly adenosine, is

B

Figure 5-12 Echocardiogram enhanced with intravenous ultrasound contrast agent (A, apical four-chamber view; B, apical long-axis view). Highly echo-reflectant microbubbles make the left ventricular cavity appear white, whereas the myocardium appears dark. See Web Figure 5-3 for a dynamic image of echocardiographic contrast. (Image courtesy of Sheldon E. Litwin, MD, Division of Cardiology, University of Utah.)

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LA V

LA

V MV

LV

A

B

Figure 5-13 Transesophageal echocardiogram demonstrating the presence of a vegetation adherent to the ring of a bi-leaflet tilting-disk mitral valve prostheses (A, systole, leaflets closed with vegetation seen in left atrium; B, diastole, leaflets open, vegetation prolapsing into left ventricle). Transesophageal echocardiography is the diagnostic test of choice for assessing prosthetic mitral valves because the esophageal window allows unimpeded views of the atrial surface of the valve. LA, left atrium; LV, left ventricle; MV, prosthetic mitral valve disks; V, vegetation. See Web Figure 5-4 for a dynamic transesophageal echocardiographic image. (Image courtesy of Sheldon E. Litwin, MD, Division of Cardiology, University of Utah.)

used as the coronary vasodilator. Each agent can increase myocardial blood flow by fourfold to fivefold. Adenosine is more expensive, but has the advantage over Persantine of a very short half-life. Newer adenosine-like agents with reduced side-effect profiles are starting to be used clinically. Technetium-99m sestamibi is the most frequently used radionuclide and is usually injected just before completion of the stress test. Tomographic (single-photon emission computed tomography [SPECT]) images of the heart are obtained for qualitative and quantitative analyses at rest and after stress. In the normal heart, radioisotope is relatively equally distributed throughout the myocardium. In patients with ischemia, a localized area of decreased uptake will occur after exercise but partially or completely fill in at rest (redistribution). A persistent defect at peak exercise and rest (fixed defect) is consistent with MI or scarring. However, in some patients with apparently fixed defects, repeat rest imaging at 24 hours or after reinjection of a smaller quantity of isotope will demonstrate improved uptake, indicating the presence of viable, but severely ischemic, myocardium. The use of new approaches such as combined low-level exercise and vasodilators, prone imaging, attenuation correction, and computerized data analysis has improved the quality and reproducibility of the data from these studies. Myocardial perfusion imaging may also be combined with ECG-gated image acquisition to allow for simultaneous assessment of ventricular function and perfusion. Not only can LVEF be quantitated with this technique, but also regional wall motion can be assessed to help rule out artifactual perfusion defects (Web Fig. 5-5). Positron-emission tomography (PET) is a noninvasive method of detecting myocardial viability by the use of both perfusion and metabolic tracers. In patients with left ventricular dysfunction, the presence of metabolic activity in a region of myocardium supplied by a severely stenotic coronary artery suggests viable tissue that may regain more

normal function after revascularization (Fig. 5-14). PET is less widely available than conventional SPECT imaging; however, PET offers improved spatial resolution because of the higher energy of the isotopes used for this type of imaging.

CARDIAC CATHETERIZATION Cardiac catheterization is an invasive technique in which fluid-filled catheters are introduced percutaneously into the arterial and venous circulation. This method allows for the direct measurement of intracardiac pressures and oxygen saturation and, with the injection of a contrast agent, visualization of the coronary arteries, cardiac chambers, and great vessels. Cardiac catheterization is generally indicated when a clinically suggested cardiac abnormality requires confirmation and its anatomic and physiologic importance needs to be quantified. In the current era, coronary angiography for the diagnosis of CAD is the most common indication for this test. Noninvasive testing, compared with catheterization, is safer, cheaper, and equally effective in the evaluation of most valvular and hemodynamic questions. Most often, catheterization will precede some type of beneficial intervention, such as coronary artery angioplasty, coronary bypass surgery, or valvular surgery. Although cardiac catheterization is generally safe (0.1% to 0.2% overall mortality rate), procedure-related complications such as vascular injury, renal failure, stroke, and MI can occur. An important objective during the cardiac catheterization is to document the filling pressures within the heart and great vessels. This task is accomplished through use of fluidfilled catheters that transmit intracardiac pressures to a transducer that displays the pressure waveform on an oscilloscope. During a right ventricular heart catheterization, pressures within the right atrium, right ventricle, and pulmonary artery are routinely measured in this manner. The


59

[13N]-ammonia

[18F]-deoxyglucose

[13N]-ammonia

[18F]-deoxyglucose

[13N]-ammonia

[18F]-deoxyglucose

Figure 5-14 Resting myocardial perfusion (obtained with [13N]-ammonia) and metabolism (obtained with [18F]-deoxyglucose) Positron-emission tomography images of a patient with ischemic cardiomyopathy. The study demonstrates a perfusion-metabolic mismatch (reflecting hibernating myocardium) in which large areas of hypoperfused (solid arrows) but metabolically viable (open arrows) myocardium are involving the anterior, septal, and inferior walls and the left ventricular apex. See Web Figure 5-5 for a dynamic image obtained with cardiac single-photon emission computed tomography imaging. (Courtesy of Marcelo F. Di Carli, MD, Brigham and Women’s Hospital, Boston.)

catheter can then be advanced further until it wedges in the distal pulmonary artery. The transmitted pressure measured in this location originates from the pulmonary venous system and is known as the pulmonary capillary wedge pressure. In the absence of pulmonary venous disease, the pulmonary capillary wedge pressure reflects left atrial pressure and, similarly, if no significant mitral valve pathologic condition exists, reflects left ventricular diastolic pressure. A more direct method of obtaining left ventricular filling pressures is to advance an arterial catheter into the left ventricular cavity. With these two methods of obtaining intracardiac pressures, each chamber of the heart can be assessed and the gradients across any of the valves determined (Fig. 5-15). Cardiac output can be determined by one of two widely accepted methods: the Fick oxygen method and the indicator dilution technique. The basis of the Fick method

is that total uptake or release of a substance by an organ is equal to the product of blood flow to that organ and the concentration difference of that substance between the arterial and venous circulation of that organ. If this method is applied to the lungs, the substance released into the blood is oxygen; if no intrapulmonary shunts exist, pulmonary blood flow is equal to systemic blood flow or cardiac output. Thus the cardiac output can be determined by the following equation: Cardiac output = oxygen consumption (arterial oxygen content − venous oxygen content ) Oxygen consumption is measured in milliliters per minute by collecting the patient’s expired air over a known period while simultaneously measuring oxygen saturation in a

60


mm Hg

200

100

LV

AO

20

Figure 5-15 Electrocardiographic and left ventricular (LV) and aortic (AO) pressure curves in a patient with aortic stenosis. A pressure gradient occurs across the aortic valve during systole.

sample of arterial and mixed venous blood (arterial and venous oxygen content, respectively, measured in milliliters per liter). The cardiac output is expressed in liters per minute and then corrected for body surface area (cardiac index). The normal range of cardiac index is 2.6 to 4.2 L/min/m2. Cardiac output can also be determined by the indicator dilution technique, which most commonly uses cold saline as the indicator. With this method, cold saline is injected into the blood, and the resulting temperature change downstream is monitored. This action generates a curve in which temperature change is plotted over time, and the area under the curve represents cardiac output. Detection and localization of intracardiac shunts can be performed by sequential measurement of oxygen saturation in the venous system, right side of the heart, and two main pulmonary arteries. In patients with left-to-right shunt flow, an increase in the oxygen saturation, or step-up, will occur as one sample from the chamber where arterial blood is mixing with venous blood. By using the Fick method for calculating blood flow in the pulmonary and systemic systems, the shunt ratio can be calculated. Noninvasive approaches have large supplanted catheterization laboratory assessment of shunts. Left ventricular size, wall motion, and ejection fraction can be accurately assessed by injecting contrast into the left ventricle (left ventriculography). Aortic and mitral valve insufficiency can be qualitatively assessed during angiography by observing the reflux of contrast medium into the left ventricle and left atrium, respectively. The degree of valvular stenosis can be determined by measuring pressure gradients across the valve and determining cardiac output (Gorlin formula). The coronary anatomy can be defined by injecting contrast medium into the coronary tree. Atherosclerotic lesions appear as narrowing of the internal diameter (lumen) of the vessel. A hemodynamically important stenosis is defined as 70% or more narrowing of the luminal diameter. However, the hemodynamic significance of a lesion can be underesti-

mated by coronary angiography, particularly in settings in which the atherosclerotic plaque is eccentric or elongated. Use of intravascular ultrasound, Doppler flow wires, or miniaturized pressure sensors can be used during invasive procedures to help evaluate the severity or estimate the physiologic significance of intermediate lesions. Biopsy of the ventricular endomyocardium can be performed during cardiac catheterization. With this technique, a bioptome is introduced into the venous system through the right internal jugular vein and guided into the right ventricle by fluoroscopy. Small samples of the endocardium are then taken for histologic evaluation. The primary indication for endomyocardial biopsy is the diagnosis of rejection after cardiac transplantation and documentation of cardiac amyloidosis; however, endomyocardial biopsy may have some use in diagnosing specific etiologic agents responsible for myocarditis.

RIGHT VENTRICULAR HEART CATHETERIZATION A right ventricular heart catheterization can be performed at the bedside with a balloon-tipped pulmonary artery (Swan-Ganz) catheter. This technique allows for serial measurements of right atrial, pulmonary artery, and pulmonary capillary wedge pressures as well as cardiac output by thermodilution (Fig. 5-16). Such measurements may be useful in monitoring the response to various treatments, such as diuretic therapy, inotropic agents, and vasopressors (Table 5-4). The pulmonary artery catheter is most useful in the critically ill patient for assessing volume status and differentiating cardiogenic from noncardiogenic pulmonary edema. Notably, however, several papers have suggested no improvements in outcomes of critically ill patients in whom pulmonary artery catheterization was performed. Improvements in noninvasive imaging techniques have made the pulmonary artery catheter much less important in diag nosing cardiac conditions, such as pericardial tamponade, constrictive pericarditis, right ventricular infarction, and ventricular septal defect.

MAGNETIC RESONANCE IMAGING Magnetic resonance angiography or imaging (MRI) is an increasingly used noninvasive method for studying the heart and vasculature, especially in patients who have contraindications to standard contrast angiography. MRI offers highresolution dynamic and static images of the heart that can be obtained in any plane. Good-quality images can be obtained in a higher number of subjects than is typically possible with echocardiography. Obesity, claustrophobia, inability to perform multiple breath-holds of 10 to 20 seconds, and arrhythmias are all causes of reduced image quality. Currently, the presence of cardiac pacemakers or implantable defibrillators is considered a contraindication for MRI. Magnetic resonance angiography is useful in the evaluation of cerebral, renovascular, and lower extremity arterial disease. MRI offers significant advantages over other imaging techniques for the characterization of different tissues (e.g., muscle, fat, scar). MRI is useful in the evaluation of ischemic heart disease because stress-rest myocardial perfusion (Fig. 5-17A) and areas of prior infarction


61

A

ECG

B Radial artery pressure (mm Hg)

100

0

C Pulmonary capillary wedge pressure (mm Hg)

40

20

0

D Right atrial pressure (mm Hg)

20

10

0 Figure 5-16 Electrocardiographic (ECG) and Swan-Ganz flotation catheter recordings are shown in tracings A and C, respectively. The left portion of tracing C was obtained with the balloon inflated, yielding the pulmonary arterial wedge pressure. The right portion of tracing C was recorded with the balloon deflated, depicting the pulmonary arterial pressure. In this patient, the pulmonary arterial wedge pressure (left ventricular filling pressure) is normal, and the pulmonary artery pressure is elevated because of lung disease.

(see Fig. 5-17B to D) can be visualized with excellent special resolution. The presence of delayed gadolinium contrast enhancement within the myocardium is characteristic of scar or permanently damaged tissue (Web Fig. 5-6). The greater the transmural extent of delayed enhancement in a given segment, the lower is the likelihood of improved function in that segment after revascularization. Because of the better spatial resolution, delayed enhancement imaging can depict localized or subendocardial scars that are not detectable with nuclear imaging techniques. The combined use of stress-rest perfusion and delayed enhancement imaging

has performance characteristics for diagnosing CAD that are at least as good as, and probably superior to, those of conventional stress tests using nuclear scintigraphy or echocardiography. MRI is excellent for evaluating a variety of cardiomyopathies (Fig. 5-18). In addition to morphology and function, characteristic patterns of delayed enhancement have been reported in myocarditis, hypertrophic cardiomyopathy, and cardiac amyloidosis. MRI has also been used to help assess right ventricular morphology and function in patients with suspected arrhythmogenic right ventricular cardiomyopathy.

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Table 5-4 Differential Diagnosis Using a Bedside Balloon Flow-Directed (Swan-Ganz) Catheter Disease State

Thermodilution Cardiac Output

PCW Pressure

RA Pressure

Comments

Cardiogenic shock Septic shock (early)

↓ ↑

↑ ↓

nl or ↓ ↓

Volume overload Volume depletion Noncardiac pulmonary edema Pulmonary heart disease RV infarction Pericardial tamponade

nl or ↑ ↓ nl

↑ ↓ nl

↑ ↓ nl

↑ Systemic vascular resistance ↑ Systemic vascular resistance; myocardial dysfunction can occur late — — —

nl or ↑ ↓ ↓

nl ↓ or nl nl or ↑

↑ ↑ ↑

Papillary muscle rupture Ventricular septal rupture

↓ ↑

↑ ↑

nl or ↑ nl or ↑

↑ PA pressure — Equalization of diastolic RA, RV, PA, and PCW pressure Large v waves in PCW tracing Artifact caused by RA → PA sampling higher in PA than RA; may have large v waves in PCW tracing

↑, Increased; ↓, decreased; nl, normal; PA, pulmonary artery; PCW, pulmonary capillary wedge; RA, right atrium; RV, right ventricle.

A

B

C

D

Figure 5-17 Cardiac magnetic resonance imaging (MRI) showing use of cardiac MRI in evaluation of cardiomyopathies. A, Severe left ventricular hypertrophy in a patient with hypertrophic cardiomyopathy. Diastolic frame shows open mitral valve. B, Systolic frame showing systolic anterior motion of mitral valve with flow disturbance in left ventricular outflow tract. C, Patient with left ventricular noncompaction as evidenced by deep trabeculations in the left ventricular apex. D, Patient with ischemic cardiomyopathy who has transmural apical infarction and adjacent mural thrombus. See Web Figure 5-6 for a dynamic cardiac MRI image. (Images courtesy of Sheldon E. Litwin, MD, Division of Cardiology, University of Utah.)

COMPUTED TOMOGRAPHY OF THE HEART New applications of computed tomography (CT) have greatly advanced our ability to diagnose cardiovascular disease noninvasively. The development of fast gantry rotation speeds and the addition of multiple rows of detectors

(multidetector CT) has allowed unprecedented visualization of the great vessels, heart, and coronary arteries with images acquired during a single breath-hold (10 to 15 seconds). Until recently, CT has been used most frequently to diagnose aortic aneurysm and acute aortic dissection and pulmonary embolism. CT is also useful for defining con-


A

B

C

D

63

Figure 5-18 Use of cardiac magnetic resonance imaging in the evaluation of chest pain or ischemic heart disease. A, First-pass perfusion study during vasodilator stress showing large septal perfusion defect. The hypoperfused area appears dark compared with the myocardium with normal perfusion. B, Example of delayed enhancement imaging with nearly transmural infarction of the mid-inferolateral wall, including the posterior papillary muscle. Infarcted myocardium appears white, whereas normal myocardium is black. C, Nontransmural (subendocardial) infarction of the septum and apex. D, Patient with acute myocarditis mimicking an acute coronary syndrome. Mid-myocardial, rather than subendocardial, delayed enhancement is characteristic of myocarditis.

genital abnormalities and detecting pericardial thickening or calcification associated with constrictive pericarditis. More recently, ECG-gated dynamic CT images have been used to quantify ventricular size, function, and regional wall motion (Web Fig. 5-7), and in contrast to echocardiography, CT is not limited by the presence of lung disease or chest wall deformity. However, obesity and the presence of prosthetic materials (i.e., mechanical valves or pacing wires) may affect image quality. The greatest excitement and controversy over cardiac CT relates to the evaluation of coronary atherosclerosis. Electron-beam and multidetector CT scans can be used to quickly and reliably visualize and quantitate the extent of coronary artery calcification (Fig. 5-19). The presence of coronary calcium is pathognomonic of atherosclerosis, and the extent of coronary calcium (usually reported as an Agatston score) is a powerful marker of future cardiac events. The coronary calcium score adds substantial, independent

improvement in risk prediction to the commonly employed clinical risk scores (e.g., the Framingham risk score). Although the extent of coronary artery calcification does not reliably predict the severity of stenoses, the calcium score is a good marker of the overall atherosclerotic burden. Contrast-enhanced coronary computed tomographic angiography (CTA) has improved dramatically in recent years. Coronary CTA has been reported to have a sensitivity of more than 95% in diagnosing significant coronary artery obstruction. This is superior to the sensitivity of stress echo or nuclear myocardial perfusion scanning. Given the speed and accuracy of this test, it is likely to assume a major role in the evaluation of patients with acute chest pain syndromes. Some advocates of cardiac CT have proposed the use of this test for the triple rule-out in patients with acute chest pain—namely, the ability to diagnose pulmonary embolism, aortic dissection, and coronary artery disease with one imaging study. Formal evaluation of this hypoth-

64


A

B

C

D

E

F

Figure 5-19 Computed tomographic coronary angiography compared with conventional radiographic contrast angiography. A and B, Volume-rendering technique demonstrating stenosis of the right coronary artery and normal left coronary artery. C and D, Maximal intensity projection of the same arteries demonstrating severe noncalcified plaque in the right coronary artery with superficial calcified plaque. E and F, Invasive angiography of the same arteries. (From Raff GL, Gallagher MJ, O’Neill WW, et al: Diagnostic accuracy of noninvasive coronary angiography using 64-slice spiral computed tomography. J Am Coll Cardiol 46:552, 2005.)

esis still needs to be undertaken. Detractors of cardiac CT most frequently cite the risks of radiation and contrast exposure as well as a lack of prospective studies showing improvement in outcome with this testing modality. Of note, the calculated radiation exposure of a cardiac CTA is about double that of a diagnostic invasive coronary angio gram, but is similar to that of a typical nuclear myocardial perfusion scan. As of this writing, the future role of cardiac CTA in routine clinical practice remains uncertain.

NONINVASIVE VASCULAR TESTING Assessment for the presence and severity of peripheral vascular disease is an important component of the cardiovascular evaluation. Comparison of the systolic blood pressure in the upper and lower extremities is one of the simplest tests to detect the presence of hemodynamically important arterial disease. Normally, the systolic pressure in the thigh is similar to that in the brachial artery. An ankle-to-brachial

Chapter 5—Diagnostic Tests and Procedures in the Patient with Cardiovascular Disease pressure ratio (ankle-brachial index) of less than or equal to 0.9 is abnormal. Patients with claudication usually have an index ranging from 0.5 to 0.8, and patients with rest pain have an index less than 0.5. In some patients, measuring the ankle-brachial index after treadmill exercise may be helpful in identifying the importance of borderline lesions. During normal exercise, blood flow increases to the upper and lower extremities and decreases in peripheral vascular resistance, whereas the ankle-brachial index remains unchanged. In the presence of a hemodynamically significant lesion, the increase in systolic blood pressure in the arm is not matched by an increase in blood pressure in the leg. As a result, the ankle-brachial index will decrease, the magnitude of which is proportional to the severity of the stenosis. After significant vascular disease in the extremities has been identified, plethysmography can be used to determine the location and severity of the disease. With this method, a pneumatic cuff is positioned on the leg or thigh and, when inflated, temporarily obstructs venous return. Volume

65

changes in the limb segment below the cuff are converted to a pressure waveform, which can then be analyzed. The degree of amplitude reduction in the pressure waveform corresponds to the severity of arterial disease at that level. Doppler ultrasound uses reflected sound waves to identify and localize stenotic lesions in the peripheral arteries. This test is particularly useful in patients with severely calcified arteries, in whom pneumatic compression is not possible and ankle-brachial indices are inaccurate. In combination with real-time imaging (duplex imaging), this technique is useful in assessing specific arterial segments and bypass grafts for stenotic or occlusive lesions. Both magnetic resonance angiography and CTA allow high-quality and comprehensive imaging of the entire peripheral arterial circulation in a single study. The threedimensional nature of these studies and their ability to perform extensive postprocessing views (including crosssectional views) of any vessel, even those that are very tortuous, are attractive features of these modalities.

Prospectus for the Future Multidisciplinary teams consisting of cardiologists, cardiac surgeons, vascular surgeons, and radiologists will replace existing and traditional approaches for the evaluation and management of patients with cardiac disease. Such collaboration will foster efficiency and rapid advances for improvements in patient care, education, and research within a seamless, integrated environment. Career opportunities within organiza-

References Cheitlin MD, Armstrong WF, Aurigemma GP, et al: ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography—summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). J Am Soc Echocardiogr 16:1091-1110, 2003. Eagle KA, Berger PB, Calkins H, et al: ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery—executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation of Noncardiac Surgery). Circulation 105:1257-1267, 2002. Gibbons RJ, Abrams J, Chatterjee K, et al: ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina). Circulation 107:149-158, 2003.

tions with the supporting infrastructure for cardiac imaging will likely realize the promise for patient-oriented, team-based cardiovascular medicine. Tissue enhancement using MRI of either the atria or ventricles will assist practitioners with classification and forecasting of outcomes after interventions such as ablation for atrial fibrillation.

Gibbons RJ, Balady GJ, Bricker JT, et al: ACC/AHA 2002 guideline update for exercise testing—summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol 40:1531-1540, 2002. Klein C, Nekolla SG: Assessment of myocardial viability with contrast-enhanced magnetic resonance imaging: Comparison with positron emission tomography. Circulation 105:162-167, 2002. Morey SS: ACC and AHA update guidelines for coronary angiography. American College of Cardiology. American Heart Association. Am Fam Physician 60:1017-1020, 1999. Raff GL, Goldstein JA: Coronary angiography by computed tomography. J Am Coll Cardiol 49:1830-1833, 2007. Sandham JD, Hull RD, Brant RF, et al: A randomized, controlled trial of the use of pulmonary artery catheters in high-risk surgical patients. N Engl J Med 348:5-14, 2003.

III

Chapter

6

Heart Failure and Cardiomyopathy Sheldon E. Litwin and Ivor J. Benjamin

T

he syndrome of heart failure occurs when an abnormality of cardiac function results in failure to provide adequate blood flow to meet the metabolic needs of the body’s tissues and organs or in an excessive rise in cardiac filling pressures. In most cases, myocardial dysfunction causes impaired ventricular filling, as well as emptying. Heart failure can result from a large number of heterogeneous disorders (Table 6-1). Idiopathic cardiomyopathy is defined as a primary abnormality of myocardial tissue in the absence of coronary occlusive, valvular, or systemic disease. However, in the clinical setting, the term cardiomyopathy is often used to refer to myocardial dysfunction that is the result of a known genetic, cardiac, or systemic disease. These secondary cardiomyopathies may be related to a significant number of disorders, but in the United States, they are most often the result of ischemic heart disease. Ventricular dysfunction can also result from excessive pressure overload, such as with long-standing hypertension or aortic stenosis, or volume overload, such as aortic insufficiency or mitral regurgitation. Diseases that result in infiltration and replacement of normal myocardial tissue, such as amyloidosis, are rare causes of heart failure. Hemochromatosis can cause a dilated cardiomyopathy that is believed to result from iron-mediated mitochondrial damage. Diseases of the pericardium, such as chronic pericarditis or pericardial tamponade, can impair cardiac function without directly affecting the myocardial tissue. Long-standing tachyarrhythmias have been associated with myocardial dys function that is often reversible. In addition, an individual with underlying myocardial or valvular disease may develop heart failure with the acute onset of an arrhythmia. Finally, multiple metabolic abnormalities (e.g., thiamine deficiency, thyrotoxicosis), drugs (e.g., alcohol, doxorubicin), and toxic chemicals (e.g., lead, cobalt) can damage the myocardium.

66

Forms of Heart Failure Heart failure can be classified as predominantly left or right sided, high output or low output, and acute or chronic. High-output failure is an uncommon disorder that can occur with severe anemia, vascular shunting, or thyrotoxicosis. This failure results when the heart is unable to meet the abnormally elevated metabolic demands of the peripheral tissues even though cardiac output is elevated. Fluid retention is a common component of this syndrome. Lowoutput failure is much more common than high-output failure and is characterized by insufficient forward output, particularly during times of increased metabolic demand. Cardiac dysfunction may predominantly affect the left ventricle, as with a large myocardial infarction, or the right ventricle, as with an acute pulmonary embolus; however, in many disease states, both ventricles will be impaired (biventricular heart failure). Acute heart failure usually refers to the situation in which an individual who was previously asymptomatic develops heart failure signs or symptoms following an acute injury to the heart, such as myocardial infarction, myocarditis, or rupture of a heart valve. Chronic heart failure refers to the situation in which an individual whose symptoms have developed over a long period, most often when preexisting cardiac disease is present. However, a patient with myocardial dysfunction from any cause may be well compensated for long periods and then develop acute heart failure symptoms in the setting of arrhythmia, anemia, hypertension, ischemia or infection. The severity of heart failure symptoms does not correlate closely with the usual clinical measures of cardiac function (i.e., left ventricular ejection fraction [LVEF]), although the LVEF is a good prognostic marker. This situation likely reflects the fact that ventricular filling pressures are a more important determinant of symptoms than myocardial

Chapter 6—Heart Failure and Cardiomyopathy Table 6-1 Causes of Congestive Heart Failure and Cardiomyopathy Coronary Artery Disease Acute ischemia Myocardial infarction Ischemic cardiomyopathy with hibernating myocardium Idiopathic Idiopathic dilated cardiomyopathy* Idiopathic restrictive cardiomyopathy Peripartum Pressure Overload Hypertension Aortic stenosis Volume Overload Mitral regurgitation Aortic insufficiency Anemia Atrioventricular fistula Toxins Ethanol Cocaine Doxorubicin (Adriamycin) Methamphetamine Metabolic-Endocrine Thiamine deficiency Diabetes Hemochromatosis Thyrotoxicosis Obesity Hemochromatosis Infiltrative Amyloidosis Inflammatory Viral myocarditis Hereditary Hypertrophic Dilated *Genetic bases for these cardiomyopathies have been identified in a large number of individual patients and families. Most of the mutations have been found in cardiac contractile or structural proteins.

function per se. Heart failure may occur in the setting of a reduced or preserved ejection fraction (EF). Recent data suggest that when sensitive methods for assessing myocardial function (i.e., tissue velocity or strain rate imaging) are used, changes are usually detected in both systolic and diastolic function in patients with heart failure (even when the EF is normal or near normal). Importantly, the pre disposing conditions for heart failure (e.g., hypertension, advanced age, coronary artery disease, renal dysfunction) are similar, the prognosis is similar irrespective of whether the LVEF is preserved or reduced. Despite many similarities, medical treatments that have been proved beneficial in heart failure with reduced EF have not shown similar efficacy in heart failure with preserved ejection fraction.

ACUTE PULMONARY EDEMA In patients with the acute onset of pulmonary edema, initial management should be directed at improving oxygenation

67

and providing hemodynamic stability. These patients commonly have marked elevation of blood pressure, cardiac ischemia, and worsening mitral regurgitation as contributing factors to the pulmonary edema. Standard therapy includes supplemental oxygen and an intravenous loop diuretic. Sublingual or intravenous nitroglycerin helps reduce preload through venodilation and may provide symptomatic relief in patients with ischemic and nonischemic ventricular dysfunction. Intravenous morphine acts in a similar manner but must be used with caution, given its depressive effects on respiratory drive. In patients with hypertensive urgency, severe hypertension, or congestive heart failure related to aortic or mitral regurgitation, an arterial vasodilator, such as nitroprusside, may be helpful in reducing afterload. Evaluation of the patient’s response to treatment requires frequent assessments of blood pressure, heart rate, endorgan perfusion, and oxygen saturation. In patients with persistent hypoxia or respiratory acidosis, mechanical ven tilation or external ventilatory support may be necessary. Pulmonary artery catheterization may be helpful in documenting filling pressures, cardiac output, and peripheral vascular resistance and in monitoring the response to therapy, although invasive monitoring has not been associated with improved patient outcomes. In patients with refractory pulmonary edema or systemic hypotension, an inotropic agent, an intra-aortic balloon pump, or a ventricular assist device may be necessary.

HEART FAILURE WITH PRESERVED EJECTION FRACTION Slowed relaxation of the left ventricle and increased chamber stiffness impair ventricular filling and may contribute to elevated left ventricular, left atrial, and pulmonary venous pressures. Diastolic filling abnormalities contribute to heart failure symptoms in most patients with reduced left ventricular function. However, some patients with a diagnosis of heart failure have normal or nearly normal EF. These patients have been commonly labeled as having diastolic heart failure. As described earlier in this chapter, newer imaging techniques have revealed that most of these patients also have a component of systolic dysfunction as well. Thus, the term heart failure with preserved EF is now the preferred terminology to describe this condition. Relaxation abnormalities are present in most people older than 65 years and are almost universal after age 75 years; however, most of these individuals do not have heart failure. Thus, isolated abnormalities of left ventricular relaxation are apparently not sufficient to directly cause heart failure in the absence of other predisposing conditions. In patients with a variety of cardiovascular diseases, relaxation abnormalities appear at earlier ages than would otherwise be expected. As of this writing, no therapeutic agents that specifically target impaired relaxation have been developed. β–Receptor agonists (dobutamine) and phosphodiesterase inhibitors (milrinone) have potent lusitropic effects (improve relaxation); however, they also directly increase contractility and enhance myocyte calcium cycling. Chronic β-blocker therapy is associated with parallel improvements in systolic and diastolic function, even though both of these may actually deteriorate during the early phases of treatment. Although calcium channel blockers have been

68


proposed as therapy for diastolic abnormalities, little evidence supports their use for this purpose. Moreover, calcium entry into cardiac myocytes through L-type calcium channels occurs almost exclusively during systole; thus, the theoretical basis for their use is also not firm. In general, all therapies that result in improved systolic function also tend to improve diastolic function, or at least diastolic filling pressures. The use of diuretics to control volume overload and the vigorous treatment of hypertension are the mainstay of therapy for this condition.

RESYNCHRONIZATION THERAPY Interventricular conduction delays, demonstrated as a prolonged QRS duration, are a common complication in patients with heart failure and have been associated with reduced exercise capacity and a poor long-term prognosis. Biventricular pacing or resynchronization therapy results in more normal ventricular contraction and has been associated with an improvement in cardiac output and LVEF. Biventricular pacing may have a beneficial effect on left ventricular remodeling by reducing left ventricular volume, left ventricular mass, and severity of mitral regurgitation. Clinically, these hemodynamic and structural changes have translated into an improvement in exercise duration, functional capacity, and quality of life. Biventricular pacing has also been shown to reduce mortality. Unfortunately, up to 30% of patients undergoing biventricular pacemaker placements do not respond favorably to the treatment. At present, this therapy is generally reserved for patients with severe heart failure and a widened QRS complex who remain symptomatic despite optimal pharmacologic therapy. Intense research efforts are underway to identify with increased accuracy the patients who are likely to derive the greatest benefit. Efforts are currently focused on the quantification of mechanical asynchrony using newer imaging techniques including tissue Doppler imaging and strain imaging (echocardiography or magnetic resonance imaging), wall thickening analysis by computed tomography, and phase imaging with nuclear scintigraphy. Resynchronization therapy is indicated for ambulatory patients with sinus rhythm and class III or IV symptoms. This therapy has not been well studied in patients with atrial fibrillation. Because of the significant expense of this treatment, it is not currently recommended for patients with short life expectancy, including those with refractory, decompensated heart failure.

Adaptive Mechanisms in Heart Failure A large number of compensatory changes occur in the cardiovascular and renal systems to maintain adequate blood flow to the vital organs of the body in the setting of myocardial dysfunction. These changes include increases in left ventricular volume and pressure through the Frank-Starling mechanism, ventricular remodeling, and neurohormonal activation. In the normal heart, increasing the stroke volume or heart rate can augment cardiac output. Stroke volume is dependent on the contractile state of the myocardium, left

Pathophysiology of Heart Failure

Myocardial damage or injury (ischemia, HTN, myocarditis, toxin, etc.)

Neuroendocrine activation (SNS, RAS)

Myocyte hypertrophy, fibrosis, chamber remodeling

Contractility and relaxation Figure 6-1 Schematic diagram illustrating the progressive nature of left ventricular dysfunction that can follow an initial cardiac insult. Attenuation of the neurohumoral activation (or blockade of the downstream effects) may interrupt the positive feedback and slow or reverse the progression of heart failure. HTN, hypertension; RAS, renin-angiotensin system; SNS, sympathetic nervous system.

ventricular filling (preload), and resistance to left ventricular emptying (afterload). According to the Frank-Starling law (Fig. 6-1), stroke volume can be increased with minimal elevation in left ventricular pressure as long as contractility is normal and outflow is not impeded. In the failing heart with depressed intrinsic contractility (Fig. 6-2, curve A), larger increases in filling pressures are required to produce similar increases in stroke volume. When left ventricular diastolic pressure approaches 20 to 25 mm Hg, the hydrostatic pressure in the pulmonary capillaries exceeds the oncotic pressure, and pulmonary edema may ensue. Both depressed myocardial contractility and increased chamber stiffness can lead to pulmonary congestion through similar mechanisms. The failing heart may also undergo changes in left ventricular size, shape, and mass to maintain adequate forward flow. This process is known as remodeling and occurs in response to myocyte loss, such as after a myocardial infarction, or to hemodynamic overload, such as aortic or mitral valve insufficiency. The initial response to increased cardiac stress or load is usually hypertrophy of the viable myocytes. If the increase occurs mainly in cell length, then ventricular dilation is the predominant form of remodeling (usually seen in volume overload or myocardial infarction). The eccentric pattern of remodeling helps maintain cardiac output but occurs at the expense of increased ventricular wall stress. If the myocytes predominantly increase in width (as in the setting of pressure overload), the heart will tend to thicken with maintenance of cavity volume. This form of remodeling, usually referred to as concentric hypertrophy, will tend to reduce wall stress but may do so at the expense of increased filling pressures. If the extent of hypertrophy is inadequate to normalize wall stress, a vicious cycle is established. Overstretching of the myocytes can lead to an increase in myocyte death, ventricular dilation, development of a spherical left ventricular cavity, and further elevation in wall stress.

Chapter 6—Heart Failure and Cardiomyopathy

Normal

Inotropic agent or afterload reduction

Stroke volume

B C Adequate

Table 6-2 New York Heart Association Functional Classification for Heart Failure Class

Patient Symptoms

I (Mild)

No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath). Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea. Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.

D

Inadequate A

Depressed contractility

Pulmonary edema 10 20 Left ventricular end-diastolic pressure (mm Hg) Figure 6-2 Normal and abnormal ventricular function curves. When the left ventricular end-diastolic pressure acutely rises above 20 mm Hg (A), pulmonary edema often occurs. The effect of diuresis or venodilation is to move leftward along the same curve, with a resultant improvement in pulmonary congestion and with minimal decrease in cardiac output. The stroke volume is poor at any point along this depressed contractility curve; thus, therapeutic maneuvers that would raise it more toward the normal curve would be necessary to improve cardiac output significantly. Unlike the effect of diuretics, the effect of digitalis or arterial vasodilator therapy in a patient with heart failure is to move the patient into another ventricular function curve intermediately between the normal and depressed curves. When the patient’s ventricular function moves from A to B by the administration of one of these agents, the left ventricular end-diastolic pressure may also decrease because of improved cardiac function; further administration of diuretics or venodilators may shift the patient further to the left along the same curve from B to C and eliminate the risk for pulmonary edema. A vasodilating agent that has both arteriolar and venous dilating properties (e.g., nitroprusside) would shift this patient directly from A to C. If this agent shifts the patient from A to D because of excessive venodilation or administration of diuretics, then the cardiac output may fall too low, even though the left ventricular end-diastolic pressure would be normal (10 mm Hg) for a normal heart. Thus, left ventricular end-diastolic pressures between 15 and 18 mm Hg are usually optimal in the failing heart to maximize cardiac output but avoid pulmonary edema.

The mechanical changes are triggered, in part, by acti vation of several neurohormonal systems. The renin-angio tensin-aldosterone system helps maintain cardiac output through expansion of intravascular volume by promoting retention of sodium and water. Stimulating arterial vasoconstriction through the actions of angiotensin II enhances tissue perfusion. In addition, release of vasopressin will promote free water absorption by the kidney. The sympathetic nervous system helps maintain tissue perfusion by increasing arterial tone as well as increasing heart rate and ventricular contractility. Although adaptive in the short term, activation of these systems is associated with several deleterious effects, including elevation in ventricular filling pressures, depression of stroke volume secondary to an increase in peripheral vascular resistance, and stimulation of myocardial hypertrophy and left ventricular remodeling. These maladaptive changes are ultimately responsible for many of the signs and symptoms associated with congestive heart failure and provide the rationale for treatment.

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II (Mild)

III (Moderate)

IV (Severe)

From the Heart Failure Society of America © 2002 HFSA, Inc. Available at: http://www.abouthf.org/questions_stages.htm.

Countering these effects, and in response to the increase in ventricular filling pressures, the myocardial cells secrete atrial natriuretic peptide and brain natriuretic peptide (BNP). The plasma concentration of both of these hormones has been shown to increase in patients with heart failure. The measurement of serum BNP or its precursors has proved to be clinically useful in the diagnosis of heart failure. Although endogenous natriuretic peptides promote salt and water excretion by the kidneys and result in arterial vasodilation, they are relatively ineffective at reversing the maladaptive changes associated with the powerful renin-angiotensin and sympathetic nervous systems.

Evaluation of Patients with Heart Failure The history and physical examination are integral parts of the diagnosis of heart failure and the determination of its underlying or precipitating cause. One of the cardinal manifestations of left ventricular heart failure is dyspnea, which is related to elevation in pulmonary venous pressure. In patients with chronic heart failure, shortness of breath initially occurs only with exertion but may progress to occur at rest. Cardiac dyspnea is often worsened by the recumbent position (orthopnea) when increased venous return further elevates pulmonary venous pressure. Paroxysmal nocturnal dyspnea occurs after several hours of sleep and is probably caused by central redistribution of edema. If cardiac output is low but left ventricular filling pressures are normal, the patient may complain primarily of fatigue resulting from diminished blood flow to the exercising muscles. In some instances, heart failure is slow to progress, and the patient may unknowingly restrict his or her activities. Thus, the history should include an assessment not only of the patient’s symptoms but also of his or her level of activity (functional capacity; Table 6-2). Many patients complain of peripheral

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edema, usually involving the lower extremities. The edema commonly worsens during the day and decreases overnight with elevation of the legs. In patients with severe, longstanding heart failure, the edema can involve the thighs and abdomen, and ascites may develop. Importantly, peripheral edema often does not have a cardiac cause. Many of the physical findings of heart failure are related to the neurohormonal changes that help compensate for the reduced cardiac output. An increased heart rate may be present as a result of increased sympathetic tone. The pulse pressure may be narrowed secondary to peripheral vasoconstriction and low stroke volume. If left ventricular filling pressures are elevated, then crackles may be heard on auscultation of the lung fields. Elevation in right-sided filling pressures will result in distended neck veins. If the liver is also congested, firm pressure applied to the right upper quadrant will cause the jugular veins to become further engorged (hepatojugular reflux). Palpation of the precordium may reveal left ventricular enlargement. An earlydiastolic third heart sound (S3) or gallop suggests elevated atrial pressure and increased ventricular chamber stiffness. The sound results from rapid deceleration of the passive component of blood flow from the atrium into the noncompliant ventricle. An S3 can be generated from the left or right ventricle. A fourth heart sound (S4) suggests an increased atrial contribution to left ventricular filling but is not specific for heart failure. The murmurs of both mitral and tricuspid regurgitation are common in patients with congestive heart failure and may become accentuated during an acute decompensation. As stated earlier, peripheral edema is a common finding on physical examination and may be related to elevation in venous pressure or increased sodium and water retention. In bedridden patients, the edema may predominantly be in the presacral region. The electrocardiogram in patients with congestive heart failure is not specific, but it may provide insight into the

cause of the cardiac dysfunction, such as prior myocardial infarction, left ventricular hypertrophy, or significant arrhythmias. The chest radiograph may show chamber enlargement and signs of pulmonary congestion (Fig. 6-3). Treatment of heart failure will result in improvement of the vascular congestion on the chest radiograph, but these changes may lag 24 to 48 hours behind clinical improvement. Certain blood chemistries may be altered in the patient with heart failure. The serum sodium concentration may be low, owing to increased water retention with activation of the renin-angiotensin system. The use of potent diuretics is almost always partially responsible for the hyponatremia. Renal function may be impaired secondary to intrinsic kidney disease or reduced perfusion secondary to renal artery vasoconstriction and low cardiac output. Hepatic congestion is common with right ventricular heart failure and may result in elevated liver enzyme levels. Because many of the signs and symptoms of heart failure may also occur with pulmonary disease, differentiating between these two disease processes may be difficult. Initial therapy will often be directed at both potential pulmonary and cardiac causes until further testing can be performed. Echocardiography is arguably the central means for diagnostic testing in patients with suspected heart failure. This test is fast, safe, and portable and allows for noninvasive assessments of chamber sizes, systolic function, valvular function, both right and left ventricular filling pressures, and quantification of stroke volume or cardiac output. Documentation of heart size, wall thickness, and ventricular function will have important therapeutic implications in most patients (Fig. 6-4). Rapid measurement of the plasma concentration of BNP provides objective and complementary data to aid in the diagnosis of heart failure in the patient with dyspnea. Clinical studies have shown that plasma levels of BNP are elevated in patients with symptomatic left or right ventric ular dysfunction but are usually normal in patients with

Figure 6-3 A, Posteroanterior chest radiograph showing cardiomegaly. B, Lateral chest radiograph showing pulmonary vascular congestion typical of pulmonary edema.

Chapter 6—Heart Failure and Cardiomyopathy

A

71

B

LV

LA

C

LV

D

Figure 6-4 Echocardiographic examples of hypertrophic cardiomyopathy seen in long axis (A) and short axis (B) views. Note normal size of left ventricular (LV) cavity and marked thickening of interventricular septum (S) compared with posterior wall (P). In contrast, similar views in a patient with dilated cardiomyopathy (C and D) reveal a markedly enlarged left ventricular cavity with diffuse wall thinning.

dyspnea secondary to noncardiac causes. Unfortunately, a relatively large indeterminate range exists in which the test is not helpful. Advanced age and renal dysfunction also reduce the utility of the test, particularly if the BNP concentration is mildly elevated. An important point to note is that pulmonary edema may also be secondary to noncardiac causes, such as sepsis, certain pulmonary infections, drug toxicity, or neurologic injury. This syndrome, termed adult respiratory distress syndrome, can be differentiated from cardiogenic pulmonary edema by the presence of a low or normal pulmonary capillary wedge pressure. The wedge pressure can be estimated noninvasively using left ventricular filling velocities and mitral annular velocities assessed by conventional and tissue Doppler techniques. Peripheral edema may also occur in disease states other than congestive heart failure. Renal

disease, especially nephrotic syndrome, cirrhosis, and severe venous stasis disease, may be associated with peripheral edema.

Treatment Treatment of congestive heart failure should be directed not only at relieving the patient’s symptoms but also at treating the underlying or precipitating causes (Table 6-3) and preventing progression. Patients should be educated about the importance of compliance with medical therapy as well as dietary salt and fluid restriction. Rhythm disturbances, such as atrial fibrillation, may precipitate congestive heart failure and may require specific therapy. Treatment of active coronary artery disease, hypertension, or valvular disease may

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Table 6-3 Precipitants of Heart Failure Dietary (sodium and fluid) indiscretion Noncompliance with medications Development of cardiac arrhythmia Anemia Uncontrolled hypertension Superimposed medical illness (pneumonia, renal dysfunction) New cardiac abnormality (acute ischemia, acute valvular insufficiency)

relieve heart failure symptoms. In addition, correction of concomitant medical problems may help stabilize heart function.

NONPHARMACOLOGIC TREATMENT All patients with heart failure should be instructed to restrict sodium intake to about 2 g/day. Fluid intake should also be limited to avoid hyponatremia. Weight reduction in the obese patient helps reduce the workload of the failing heart. Although a growing body of data suggests that a higher body mass index may paradoxically have protective effects in patients with heart failure, each condition is an independent risk factor for increased morbidity and mortality of cardiac disease. A supervised exercise cardiac rehabilitation program can help reduce heart failure symptoms and improve functional capacity in select patients. Although briefly popular, external enhanced counterpulsation (EECP) has fallen out of favor.

PHARMACOLOGIC TREATMENT Diuretics Salt and water retention is common in congestive heart failure secondary to activation of the renin-angiotensinaldosterone system. Diuretics help promote renal excretion of sodium and water and provide rapid relief of pulmonary congestion and peripheral edema. Loop diuretics, such as furosemide, are the preferred agents in the treatment of symptomatic heart failure. In patients who are refractory to high doses of these agents, diuretics that block sodium absorption at different sites within the nephron may be beneficial (i.e., thiazide-type diuretics). Diuretic therapy is currently considered a mainstay in the treatment of patients with heart failure and preserved EF who have elevated left ventricular filling pressures or peripheral edema. Spirono lactone is an aldosterone antagonist with weak diuretic effects that has been shown to reduce hospitalizations for heart failure and cardiac mortality in patients with reduced LVEF and New York Heart Association class III or IV symptoms of heart failure. Notably, diuretic therapy will lower intracardiac filling pressures and thus cardiac output through the FrankStarling mechanism. In most patients, this change is well tolerated. However, in some patients, the reduced cardiac output will result in decreased renal perfusion and a rise in the blood urea nitrogen and creatinine levels.

Vasodilators A large number of vasodilators have been shown to reverse the peripheral vasoconstriction that occurs in congestive heart failure. The most important group of vasodilator agents is the angiotensin-converting enzyme (ACE) inhi bitors. These agents help relieve heart failure symptoms, in part, by blocking production of angiotensin II and reducing afterload. In addition, ACE inhibitors have been shown to reduce mortality in patients with both symptomatic and asymptomatic left ventricular dysfunction. The major side effects of ACE inhibitors include hypotension, hyperkalemia, and azotemia. Cough may occur in about 10% of patients and is related to increased bradykinin levels asso ciated with ACE inhibitor use. Hydralazine in combination with oral nitrates has also been shown to reduce mortality in patients with symptomatic congestive heart failure, although not to the degree of ACE inhibitors. This combination provides an alternative to the patient who is ACE inhibitor intolerant or may require additional therapy for blood pressure control. In addition, recent prospective studies reveal that the combination of hydralazine and nitrates was more beneficial than ACE inhibitors in the African American population. A newer class of agents, the angiotensin II receptor antagonists, prevents the binding of angiotensin II to its receptor. This action has the theoretical advantage of blocking the effects of angiotensin II produced in the bloodstream as well as at the tissue level. In addition, the angiotensin II receptor blockers do not interfere with bradykinin metabolism and therefore are not associated with cough. Several studies comparing ACE inhibitors to angiotensin II blockers suggest that these two classes of agents are equally effective in reducing morbidity and mortality in patients with heart failure. The current guidelines for the management of chronic heart failure, however, recommend that angiotensin II receptor blockers be reserved for patients who are intolerant of ACE inhibitors. ACE inhibitors and angiotensin II receptor blocking agents have both been studied in large randomized trials of patients with heart failure and preserved EF, and they have been found to be ineffective in this large patient group. The negative inotropic effects of the calcium channel blockers and their activation of the sympathetic nervous system make these agents less attractive in the treatment of patients with congestive heart failure. In particular, several studies have shown worsening of heart failure symptoms in patients treated with nifedipine. Other calcium channel blockers, such as diltiazem, have been shown to relieve symptoms and increase functional capacity without a deleterious effect on survival in patients with idiopathic dilated cardiomyopathy. Amlodipine has been studied in patients with both ischemic and nonischemic cardiomyopathy and also has not been associated with an increased cardiac morbidity and mortality. In addition, patients with nonischemic cardiomyopathy treated with amlodipine may have a modest survival benefit. Further studies with these agents are necessary before general recommendations regarding their use in patients with heart failure can be made.

Inotropic Agents Inotropic agents help relieve heart failure symptoms by increasing ventricular contractility. The oldest and most commonly used agent in this class is digoxin, which has been

Chapter 6—Heart Failure and Cardiomyopathy associated with symptomatic improvement in heart failure in patients with systolic dysfunction. However, a recent trial found no significant improvement in survival among patients randomized to digoxin compared with patients treated with placebo. A small reduction in hospitalizations and in death secondary to heart failure was observed, but this was counterbalanced by a slight increase in death secondary to arrhythmias. In general, digoxin therapy should be considered in the patient with left ventricular systolic dysfunction who remains symptomatic after treatment with an ACE inhibitor and a diuretic. No evidence has been found that digoxin should be administered to the patient with asymptomatic left ventricular dysfunction. In addition, digoxin may be harmful in patients with infiltrative cardiomyopathies, such as amyloidosis. Digoxin toxicity results in gastrointestinal, neurologic, and generalized systemic side effects as well as causing a number of tachyarrhythmias and bradyarrhythmias. Several other classes of oral inotropic agents have been evaluated for treatment of congestive heart failure, such as flosequinan, milrinone, vesnarinone, and xamoterol. All these agents have been associated with increased mortality with long-term use. More recently, promising data have emerged involving the calcium-sensitizing agent levosimendan. This class of agents has the theoretical advantage of not increasing calcium fluxes into the myocyte; therefore, these agents should be less arrhythmogenic and have a more favorable energetic effect.

β Blockers As previously discussed, many of the symptoms associated with heart failure are related to activation of several neurohormonal systems, including the sympathetic nervous system. Release of catecholamines may initially help maintain blood pressure and cardiac output but, in the long term, may induce further myocardial injury. To date, long-term use of three different β blockers—metoprolol, bisoprolol, and carvedilol—has been shown in clinical trials to improve LVEF and survival in patients with symptomatic left ventricular dysfunction. Of these agents, carvedilol is unique in that it is also an antioxidant and an α blocker, additional properties that may be beneficial in patients with heart failure. Data from clinical trials comparing the efficacy of metoprolol to carvedilol in patients with heart failure have recently been reported. These data suggest superior effects of carvedilol; however, controversy about the experimental design has limited widespread adoption of a single agent. Therapy with one of the aforementioned β blockers should be strongly considered in all patients who have been stabilized on an ACE inhibitor, digoxin, and a diuretic but remain symptomatic (New York Heart Association classes II to IV). β blockers also appear to be effective in patients who are not taking ACE inhibitors. β-blocker therapy is generally withheld from patients with acutely decompensated heart failure or significant volume overload. Gradual up-titration of the dose improves the ability to tolerate these drugs, which are intrinsically negatively inotropic.

Anticoagulation Thrombosis and thromboemboli occur in patients with left ventricular remodeling and congestive heart failure secondary to stasis of blood, intracardiac thrombi, and atrial

73

arrhythmias. Although long-term warfarin therapy remains controversial, certain patients may benefit from its use, including patients with chronic atrial fibrillation or flutter, patients with definite mural thrombi noted by echocardiography or ventriculography, and patients in sinus rhythm with LVEF less than 20%. In the general heart failure population, prevention of thromboembolism is roughly balanced by increased bleeding risks. Thus, the routine use of anticoagulation is only recommended in heart failure patients with atrial fibrillation, prior arterial embolic events, or mechanical heart valves and in patients who have had an anterior myocardial infarction in the past 3 months.

Refractory Heart Failure Despite adequate medical therapy, many patients with congestive heart failure fail to have significant reduction in their symptoms. In these instances, therapy with intravenous inotropic agents for 24 to 96 hours, sometimes with hemodynamic monitoring (Swan-Ganz catheter), may be necessary to stabilize the patient. One commonly used agent is dobutamine, which enhances contractility of the heart and reduces peripheral vasoconstriction through stimulation of β2 receptors. Milrinone is an intravenous phosphodies terase inhibitor that has similar effects on contractility and afterload. Administration of these agents often promotes diuresis, especially when given concomitantly with intravenous loop diuretics. In patients with markedly elevated systemic vascular resistance, the use of intravenous vasodilators, such as sodium nitroprusside, can significantly reduce afterload and improve cardiac output. A newly available agent, nesiritide, is a recombinant form of human BNP that has been shown to reduce systemic and pulmonary vascular resistance, increase cardiac output, and promote diuresis comparable to standard inotropic agents and vasodilators. Although nesiritide is less likely to provoke serious dysrhythmias compared with dobutamine, recent data have questioned the safety profile and efficacy of nesiritide. Until further studies document safety, nesiritide is not a first-line agent. If the previously mentioned measures fail to produce a satisfactory diuretic response, dopamine given in doses ranging from 2 to 5 mcg/kg per minute may facilitate sodium and water excretion by stimulating renal dopaminergic receptors. If heart failure is accompanied by hypotension, higher doses of dopamine may be necessary. With doses higher than 5 mcg/kg per minute, dopamine can increase heart rate and peripheral vascular resistance through stimulation of β1 and α receptors. Although this dose range of dopamine may help stabilize blood pressure, the increase in afterload may have further deleterious effects on the failing heart. In addition, dopamine may provoke arrhythmias that may lead to further hemodynamic instability. If hypotension persists despite dopamine doses greater than 15 mcg/kg per minute, mechanical assist devices, such as the intra-aortic balloon pump, should be considered as a means to stabilize the patient. In patients who cannot be weaned from pharmacologic or mechanical support and in ambulatory patients with severe functional impairment refractory to medical therapy, cardiac transplantation should be considered a means to improve

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symptoms and prolong survival (see Chapter 12). Currently, the use of cardiac resynchronization therapy is not a routine consideration in this group of patients who have markedly reduced long-term survival.

Cardiovascular Assist Devices The most commonly used mechanical support device is the intra-aortic balloon pump. This device can be inserted percutaneously through the femoral artery and advanced into the descending thoracic aorta. Inflation of the balloon occurs during diastole such that perfusion pressure in the proximal aorta and coronary arteries is enhanced. Deflation, which occurs just before the onset of systole, greatly reduces aortic impedance and thus significantly reduces afterload. This device is particularly useful in stabilizing patients with severe coronary disease before percutaneous or after surgical revascularization. In addition, this device may provide hemodynamic support in patients with severe mitral regurgitation

or acquired ventricular septal defect before surgical repair. In patients with refractory congestive heart failure, the intraaortic balloon pump may serve as a temporizing measure until cardiac transplantation can be performed. In addition to the intra-aortic balloon pump, several ventricular assist devices are available that provide hemodynamic support. These devices can be placed percutaneously but most commonly are implanted through a sternotomy incision. They can be used to support either ventricle. Blood is collected from the right atrium, left atrium, or the left ventricular apex into an extracorporeal reservoir and then actively pumped back into the pulmonary or systemic circulation by the assist device. These units were initially intended to provide hemodynamic support for several days to weeks (most often a bridge to transplantation in the patient who is critically ill). Because of the success with these devices and the limited availability of donor hearts, assist devices are now being implanted as destination therapy. The pump is placed within the peritoneum, and portable battery packs allow the patient to ambulate. Newer left ventricular assist devices, as well as total artificial hearts, are undergoing clinical investigation as permanent cardiac replacement therapy.

Prospectus for the Future External Containment Devices In patients with left ventricular dysfunction, cardiac remodel ing characterized by progressive ventricular chamber dilation and wall thinning can lead to elevation in wall stress and activation of neurohormonal mechanisms that further impair myocardial function. Experimental devices that passively contain the heart have been shown, in animal models, to reduce ventricular cavity size and improve myocardial responsiveness to β-adrenergic stimulation without impairing left ventricular filling or interfering with coronary blood flow. Randomized trials evaluating the efficacy of these devices in patients with end-stage cardiomyopathy are underway.

Mitral Valve Repair Mitral regurgitation contributes to the progression of heart failure in a large number of patients. However, most patients

References Burkhoff D, Maurer MS, Packer M, et al: Heart failure with a normal ejection fraction: Is it really a disorder of diastolic function? Circulation 107:656-658, 2003. Cleland JG, Daubert JD, Erdmann E, et al: The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 352:1539-1549, 2005. Dokainish H, Zoghbi WA, Lakkis NM, et al: Optimal noninvasive assessment of left ventricular filling pressures: A comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation 109:2432-2439, 2004.

with severe heart failure are deemed poor surgical candidates. Several new and exciting percutaneous approaches to mitral and aortic valve repair are being explored as ways to treat some of these patients.

Cell-Based Therapies Permanent loss of myocytes is the final common pathway in most forms of heart failure. Presently, some experimental data support the notion that implantation of cells into the failing heart might effectively regenerate new cardiac muscle. Skeletal myoblasts, bone marrow–derived progenitor cells, and embryonic stem cells are all undergoing testing in both animals and humans. Although many types of transplanted cells are able to contract, ineffective formation of gap junctions and hence ineffective electrical continuity between the transplanted cells and the existing myocardial syncytium continue to be obstacles.

Poole-Wilson PA, Swedberg K, Cleland JG, et al: Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): Randomised controlled trial. Lancet 362:7-13, 2003. Rose EA, Gelijns AC, Moskowitz AJ, et al: Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 345:1435-1443, 2001. Taylor AL, Ziesche S, Yancy C, et al: Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 351:2049-2057, 2004. Young JB, Abraham WT, Smith AL, et al: Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: The MIRACLE ICD trial. JAMA 289:2685-2694, 2003.

Chapter

7

III

Congenital Heart Disease Kevin J. Whitehead

A

bout 0.8% of all live births are complicated by congenital cardiac abnormalities, not including infants with bicuspid aortic valve and mitral valve prolapse (see Chapter 8), which are more prevalent (2% and 2.4%, respectively). Congenital heart disease is a major cause of infant morbidity and mortality. As a result of advances in pediatric cardiology and cardiothoracic surgery, about 85% of infants born with congenital heart disease can be expected to survive into adulthood. In turn, adults with congenital heart disease represent a large and growing population that is encountered more frequently in clinical practice. An equal number of adults and children live with congenital heart disease, with an estimated 800,000 adult patients in the United States alone. Most cases of congenital heart disease occur sporadically, without a known specific cause. Genetic abnormalities are responsible for a proportion of cases and may contribute to cases occurring sporadically as well. Environmental factors are also known to cause congenital heart disease. An increased incidence is found in children of patients with congenital heart disease, with a higher risk in mothers than in fathers. In most cases, the nature of the parent’s defect does not predict the lesion in affected offspring. The size and nature of the congenital defect often determine the onset of symptoms. Normal physiologic changes in cardiovascular hemodynamics at birth can prompt pre sentation. Symptoms can develop shortly after birth when transition from fetal to adult circulation represents a new dependence on biventricular circulation with a pulmonary circuit. The isolated pulmonary and systemic circulations of D-transposition of the great arteries become apparent on closure of the last fetal connections between circuits, the ductus arteriosus and the foramen ovale. In other conditions, the primary lesion results in changes that delay presentation until such compensatory mechanisms fail. Hypertrophy of the morphologic right ventricle in L-transposition of the great arteries is sufficient to com pensate for systemic vascular resistance and maintain normal perfusion for years, with symptoms often developing when the systemic ventricle fails. Still other lesions may develop in adulthood when degenerative changes, such as stenosis

of a previously well-functioning bicuspid aortic valve, are superimposed on an initial lesion. Some congenital defects may go undetected throughout life (e.g., small atrial septal defects [ASDs], whereas some may resolve spontaneously (small muscular ventricular septal defects [VSDs]). Many adult patients with congenital heart disease will have already undergone palliative or reparative surgical procedures and will have subsequent care directed at residual defects and sequelae of such procedures. This chapter focuses on the most common congenital abnormalities observed in adults, including those that develop in adulthood and those for which surgical correction during infancy and childhood permits survival into adulthood.

Septal Defects ATRIAL SEPTAL DEFECTS ASDs are some of the most common congenital defects, representing 10% to 17% of cases, with a higher prevalence in women (60%). Defects are classified according to their location in the interatrial septum. The most common ASD (60%), the ostium secundum defect, involves the fossa ovalis. Ostium primum defects (20%) involve the atrioventricular junction and are at one end of the spectrum of atrioventricular septal defects (or endocardial cushion defects). Primum ASDs are usually associated with a cleft mitral valve and mitral regurgitation. In rare cases, primum ASD can be associated with a large VSD and a single atrioventricular (AV) valve, forming an AV septal defect. Sinus venosus defects are located in the superior septum and may be associated with partially anomalous pulmonary venous drainage into the superior vena cava or right atrium. In patients with uncomplicated ASDs (e.g., with normal pulmonary vascular resistance), oxygenated blood shunts from the left to the right atrium. The magnitude of the shunting is determined by the size of the defect and the compliance of the left and right ventricles. Small ASDs accommodate the increased blood flow in the right atrium without sequelae and no significant hemodynamic compro75

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mise of the right heart. If the defect is large, the right atrium and right ventricle dilate to accommodate the increased volume of shunted blood (Fig. 7-1). Pressure in the pulmonary artery increases secondary to the increased volume of blood; however, with the exception of extremely large, long-standing defects, pulmonary vascular resistance usually remains normal.

Atrial septal defect

RA

RV

A

PA

Ventricular septal defect

LA

RA

LV

RV

AO

B

PA

LA

LV AO

Patent ductus arteriosus RA

RV

LA

LV

PA

C

AO

Figure 7-1 Diagram illustrates the three types of shunt lesions that commonly survive until adulthood and their effects on chamber size. A, Uncomplicated atrial septal defect demonstrating left-to-right shunt flow across the interatrial septum and resulting in dilation of the right atrium (RA), right ventricle (RV), and pulmonary artery (PA). B, Uncomplicated ventricular septal defect, resulting in dilation of the RV, left atrium (LA), and left ventricle (LV). C, Uncomplicated patent ductus arteriosus, resulting in dilation of the LA, LV, and PA. Ao, aorta. (From Liberthson RR, Waldman H: Congenital heart disease in the adult. In Kloner RA [ed]: The Guide to Cardiology, 3rd ed. Greenwich, Conn, Le Jacq Communications, 1991, pp 24-47. Copyright ©1991 by Le Jacq Communications, Inc.)

Most patients with ASD are asymptomatic until adulthood, when symptoms such as fatigue, dyspnea, and poor exercise tolerance develop, secondary to right ventricular dysfunction. Older patients may decompensate when acquired heart disease leads to a rise in left ventricular filling pressures and more blood is shunted from the left atrium to the already volume-overloaded right heart. Patients with ASD are prone to atrial fibrillation, especially after 50 years of age. Irreversible pulmonary vascular obstruction resulting in right-to-left shunting and cyanosis (Eisenmenger syndrome) is uncommon and occurs infrequently (180 milliseconds) on the surface electro cardiographic study is a marker for increased risk for ventricular tachycardia and sudden death. Palliative surgery may have been performed in childhood to improve pulmonary blood flow. Occasionally, patients may elect not to undergo complete repair. Such palliation involves the creation of a shunt between the systemic and pulmonary circulation (e.g., subclavian artery to ipsilateral pulmonary artery [Blalock-Taussig shunt]), which results in increased pulmonary blood flow and improved oxygenation of the systemic blood. A variety of palliative shunts have

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been used for this purpose. Although such procedures often result in long-term palliation of hypoxia, several complications can occur. Patients may outgrow their shunts, or the shunts may spontaneously close and may lead to progressive cyanosis. If the shunt is too large, the increased volume of blood into the pulmonary circulation and left heart may result in pulmonary congestion and progress to irreversible pulmonary vascular obstruction. In patients surviving to adulthood, corrective surgery should still be undertaken, but the operative risk is higher secondary to the presence of right ventricular dysfunction.

COMPLETE TRANSPOSITION OF THE GREAT ARTERIES Complete transposition (also known as D-transposition) represents 5% to 7% of congenital heart disease and is the most common cyanotic congenital heart disease in the newborn. It is characterized by abnormal ventriculoarterial connections with the aorta arising from the right ventricle and the pulmonary artery arising from the left. The circulation is thus two circuits in parallel. This anatomy can support fetal development, but serious consequences result on closure of the foramen ovale and ductus arteriosus shortly after birth, at which point the systemic and pulmonary circuits are separated and oxygenated blood no longer mixes with the systemic circulation. Uncorrected D-transposition has a 90% mortality rate in the first year of life. Associated defects include VSD, left ventricular outflow tract (subpulmonic) stenosis, and coarctation of the aorta. The first successful palliative procedure for D-transposition was the atrial switch procedure (e.g., Mustard or Senning procedures) in which the venous return is baffled to the contralateral ventricle to achieve two circuits in series. These procedures result in excellent short- and mid-term outcomes. Complications include failure of the systemic right ventricle, tricuspid regurgitation, sinus node dysfunction, tachyarrhythmias, and baffle leaks or obstruction. Progressive ventricular failure should prompt consideration of heart transplantation. In the 1980s, the arterial switch procedure supplanted the Mustard and Senning procedures. This technically challenging procedure restores normal anatomy by attaching the aorta to the left ventricle and the pulmonary artery to the right ventricle with reimplantation of the coronary arteries into the new aorta. Less long-term follow-up data are available for patients following arterial switch, but similar favorable mid-term outcomes have been noted, relative to the Mustard and Senning procedures. Late complications include obstruction of the reimplanted coronary arteries with asso ciated myocardial ischemia, and progressive enlargement of the new aortic root with associated valvular regurgitation. It is recommended that all adults be evaluated at least once for coronary artery patency following arterial switch.

CORRECTED TRANSPOSITION OF THE GREAT ARTERIES Inversion of the ventricles and abnormal positioning of the great arteries characterize congenital-corrected transposition of the great arteries (L-transposition). In this anomaly, the anatomic right ventricle lies on the left and receives oxygenated blood from the left atrium. Blood is ejected into

82


an anteriorly displaced aorta. The anatomic left ventricle lies on the right and receives venous blood from the right atrium and ejects it into the posteriorly displaced pulmonary artery. This condition is not generally cyanotic and is uncommon, representing 0.5% of cases in patients with congenital heart disease. The clinical course of patients with corrected transposition depends on the severity of other intracardiac anomalies. When the abnormality is an isolated lesion, many individuals survive into adulthood without symptoms. In some patients, the systemic ventricle (anatomic right ventricle) may fail, and pulmonary congestion may result. Associated anomalies include atrioventricular nodal block, VSD, and Ebstein anomaly.

SINGLE VENTRICLE AND FONTAN OPERATION A variety of anatomic defects can functionally result in a single ventricle supporting both the pulmonary and systemic circulation. As such, tricuspid atresia, double-inlet left ventricle with VSD, and large atrioventricular septal defect (among others) may all have similar consequences for the patient. The cardiac output is directed in common to both the aorta and the pulmonary artery, with the balance between the two circulatory beds determined by the degree of outflow tract obstruction. If outflow obstruction is equal, the lower pulmonary vascular resistance will tend to favor pulmonary flow; thus, the ideal single ventricle will have some degree of pulmonary outflow obstruction to prevent the development of fixed pulmonary hypertension. Patients with univentricular hearts who are not repaired have a poor prognosis, with a median survival of 14 years of age. Most patients have cyanosis and functional limitations and would benefit from palliative surgery. The goal with palliation is to optimize pulmonary blood flow without volume loading the ventricle. In suitable patients, the Fontan procedure can offer improved functional status and relieve cyanosis. The Fontan procedure and its modifications connect all systemic venous return to the pulmonary artery without an intervening ventricular pump. This can be accomplished by anastomosis of the right atrium to the pulmonary arteries, separate connections between the superior vena cava and the adjacent right pulmonary artery, and the inferior vena cava through a graft to the left pul monary artery or a tunnel connecting the vena cava and anastomosed to the pulmonary artery. The Fontan procedure separates the two circulations and provides relief of cyanosis without providing a volume load on the left ventricle or a pressure load on the pulmonary arteries. Complications include thrombosis, obstruction, or leaks in the Fontan circuit, ventricular dysfunction, arrhythmias, hepatic dysfunction, and protein-losing enteropathy. Patients with poor ventricular function or intractable protein-losing enter opathy after the Fontan procedure should be considered for transplantation.

EISENMENGER SYNDROME In 1897, Victor Eisenmenger first described the clinical and pathologic features of a patient with fixed pulmonary hypertension resulting from a large VSD. In 1958, Paul Wood used

the term Eisenmenger complex to describe the combination of a large VSD with systemic pulmonary pressures and a reversed or bidirectional shunt. The same pulmonary pathologic changes can result from a large shunt at any level, and the term Eisenmenger syndrome was suggested to describe pulmonary hypertension with reversed or bidirectional shunting at any level. Thus a VSD, a PDA, or an ASD could all result in Eisenmenger physiologic characteristics. The defect size generally exceeds 1.5 cm in diameter for VSD, with about half that diameter for PDA and twice that diameter for ASD. Large surgical shunts can also lead to Eisenmenger syndrome. Most patients with Eisenmenger syndrome survive to adulthood, with complications generally occurring from the third decade onward. The prognosis is better than that for patients with other causes of pulmonary hypertension such as primary pulmonary hypertension. Complications include hyperviscosity syndrome, hemorrhage or thrombosis, arrhythmias and sudden death, endocarditis and cerebral abscess, ventricular dysfunction, hyperuricemia and gout, and renal impairment, among others. Hyperviscosity syndrome results from excessive erythrocytosis driven by increased erythropoietin in response to chronic hypoxia. Symptoms include headache, myalgias, and altered mentation. Many patients can tolerate a high hematocrit level with mild or no symptoms, and phlebotomy should not be undertaken simply in response to the hematocrit level. Excessive phlebotomy can lead to iron deficiency. Iron-deficient erythrocytes are less distensible and result in higher blood viscosity for any given hematocrit level, with microcytosis being the strongest independent predictor for cerebrovascular events. Patients with Eisenmenger syndrome have achieved a delicate balance, and management of such patients should respect that balance. Prevention of complications is the preferred strategy. Influenza inoculations, endocarditis prophylaxis, and an avoidance of inappropriate phlebotomy are the mainstays of management. Extreme caution should be exercised with noncardiac surgery to avoid precipitous changes in vascular resistance that may lead to cardiovascular collapse. Pregnancy is strongly discouraged, considering the high risk to both the mother and the fetus. Sterilization is preferred because oral contraceptives can aggravate the risk for thrombosis. Pulmonary vasodilator therapy may improve quality of life, but carries recognized risks and should be supervised by expert care.

Other Conditions Congenital anomalies of the coronary arteries are not uncommon and may be asymptomatic or associated with myocardial ischemia. The left circumflex or left anterior descending artery may arise from the right sinus of Valsalva and is usually not associated with abnormalities of myocardial perfusion. Either coronary artery may arise from the right sinus and may pass between the pulmonary trunk and aorta. This abnormality may result in myocardial ischemia, infarction, or sudden death in young adults, especially during exertion. Coronary artery fistulas with drainage into the right ven tricle, vena cava, or pulmonary vein may be associated with myocardial ischemia if a significant amount of coronary blood flow is shunted into the venous system. Diagnosis of these abnormalities is made by coronary angiography.

Chapter 7—Congenital Heart Disease

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Prospectus for the Future The growing population of patients with successful outcomes after intervention for congenital heart disease is posing new challenges during adulthood. The increasing prevalence of genetic studies must be linked to genetic counseling. Early prenatal diagnoses that are linked to specific molecular defects

References Deanfield J, Thaulow E, Warnes C, et al: Management of grown up congenital heart disease. Eur Heart J 24:1035, 2003. Gatzoulis MA, Webb GD, Daubeney PEF: Diagnosis and Management of Adult Congenital Heart Disease. Philadelphia, Elsevier, 2003. Therrien J, Dore A, Gersony W, et al: Canadian Cardiovascular Society Consensus Conference 2001 update: Recommendations for the management of adults with congenital heart disease—Part I. Can J Cardiol 17:940, 2001. Therrien J, Gatzoulis M, Graham T, et al: Canadian Cardiovascular Society Consensus Conference 2001 update: Recommendations for the management of adults with congenital heart disease—Part II. Can J Cardiol 17:1029, 2001.

will engender therapeutic strategies in utero. Genetic epidemiologic studies will provide important insights about the influences of the in utero environment on the subsequent susceptibility and risk factors for heart disease during adulthood.

Therrien J, Warnes C, Daliento L, et al: Canadian Cardiovascular Society Consensus Conference 2001 update: Recommendations for the management of adults with congenital heart disease—Part III. Can J Cardiol 17:1135, 2001. Warnes CA, Williams RG, Bashore TM, et al: ACC/AHA 2008 guidelines for the management of adults with congenital heart disease. Circulation 118:e714-e833, 2008. Webb GD, Williams RG: Care of the adult with congenital heart disease. J Am Coll Cardiol 37:1166, 2001. Wilson W, Taubert KA, Gewitz M, et al: Prevention of endocarditis: Guidelines from the American Heart Association. Circulation 116:1736-1754, 2007.

III

Chapter

8

Acquired Valvular Heart Disease Sheldon E. Litwin

Aortic Stenosis Aortic stenosis can be congenital or acquired in origin (Table 8-1). The most common congenital cardiac abnormality affects the bicuspid aortic valve. Significant narrowing of the orifice usually occurs during middle age after years of turbulent flow through the valve results in leaflet injury, thickening, and calcification. Rheumatic aortic stenosis results from fusion of the leaflet commissures and is usually associated with mitral valve disease. The most common cause of aortic stenosis in adults is degenerative or senile aortic stenosis, which usually occurs in patients older than 65 years. Aortic stenosis is more common in men than it is in women. In patients with aortic stenosis, the outflow obstruction gradually increases over many years, resulting in left ventricular hypertrophy. This response allows the left ventricle to generate and maintain a large pressure gradient across the valve without a reduction in stroke volume. However, left ventricular hypertrophy often results in increased diastolic chamber stiffness because greater intracavitary pressure is required to maintain left ventricular filling. Systolic dysfunction may also occur as a result of changes in expression of myocyte contractile and calcium-cycling proteins. Patients with severe aortic stenosis may be asymptomatic for many years despite the presence of severe obstruction. The cardinal symptoms associated with aortic stenosis are angina, syncope, and congestive heart failure. Angina can occur in the absence of epicardial coronary artery disease because of the increased oxygen demand of the hypertrophied ventricle and decreased coronary blood flow secondary to elevated left ventricular diastolic pressure. Syncope may result from transient arrhythmias but more commonly occurs with exertion when cardiac output is insufficient to maintain arterial pressure in the presence of exercise-induced peripheral vasodilation. Dyspnea may result from increased filling pressures associated with the noncompliant, hypertrophied left ventricle or may signal the onset of systolic 84

dysfunction. Once patients with severe aortic stenosis develop symptoms, the prognosis is poor unless surgical correction is undertaken. Previous studies have shown that the mean survival rate after the onset of symptoms is about 2 years in patients with heart failure, 3 years in patients with syncope, and 5 years in patients with angina (Fig. 8-1). On physical examination, the patient with aortic stenosis may have a laterally displaced, sustained apical impulse secondary to left ventricular hypertrophy (Table 8-2). An audible or palpable S4 may also be present if the patient is in sinus rhythm. Decreased mobility of the aortic cusps may cause the A2 component of S2 to be soft or absent. The murmur of aortic stenosis is a harsh, crescendo-decrescendo murmur that is best heard over the right upper sternal border and often radiates to the neck. As the obstruction increases, the peak of the murmur occurs later in systole. If left ventricular dysfunction develops, the murmur may decrease in intensity secondary to a reduction in stroke volume. The carotid impulse is often diminished in intensity and delayed (i.e., pulsus parvus et tardus) (see Chapter 4), although in older adults, these changes may be present secondary to intrinsic vascular disease in the absence of significant aortic stenosis. The principal electrocardiographic finding in aortic stenosis is left ventricular hypertrophy. Heart block may develop as a result of calcification from the aortic valve extending into the conducting system. Echocardiography is the most important diagnostic test and is useful to determine the cause of the aortic stenosis and to quantitate the degree of obstruction. The mean transvalvular gradient and valve area can be measured and calculated using Doppler techniques. Patients with severe stenosis will often undergo cardiac catheterization both to confirm the presence of severe aortic stenosis and to determine whether concomitant coronary artery disease is present. A valve area less than or equal to 0.7 cm2 defines critical aortic stenosis (normal valve area is 3 cm2) and is usually associated with a mean transvalvular gradient of more than 50 mm Hg when normal left

Chapter 8—Acquired Valvular Heart Disease Table 8-1 Major Causes of Valvular Heart Disease in Adults

Aortic Regurgitation Bicuspid aortic valve Aortic dissection Endocarditis Rheumatic fever Aortic root dilation Mitral Stenosis Rheumatic fever

80 60

2 3 5 Average survival years

40

0

Average age death (male) 0

50

40

A 100

Percent survivors

Chronic Mitral valve prolapse Left ventricular dilation Posterior wall myocardial infarction Rheumatic fever Endocarditis

Tricuspid Regurgitation

Angina Syncope Failure

Latent period (increasing obstruction, myocardial overload)

20

Mitral Regurgitation

Acute Posterior wall or papillary muscle ischemia Papillary muscle or chordal rupture Endocarditis Prosthetic valve dysfunction Systolic anterior motion of mitral valve

Onset severe symptoms

100 Percent survival

Aortic Stenosis Bicuspid aortic valve Rheumatic fever Degenerative stenosis

85

60 63 Age, years

70

AI MI

(35) (70) (124) MS (120) (133) (67) (116) (68) (114) (35) (35) (64) (108) (62) (101) 75 AS(42) (35) (60) (57) (92) (35) (32) (32) (51) (82) (26) (47) (42)

(23)

(42)

50

(42) (22)

(42)

Functional (annular) dilation Tricuspid valve prolapse Endocarditis Carcinoid heart disease

(76)

(42) (41) (36) (36)

25

ventricular function is present. It should be noted that in patients with reduced systolic function, the mean gradient might be low despite the presence of severe aortic stenosis. Moreover, symptoms are often present with valve areas of 0.7 to 1 cm2. Treatment in most adults with symptomatic aortic stenosis is surgical replacement of the valve. The operative risk and prognosis are best in patients with preserved left ventricular systolic function. However, surgery should still be considered in patients with left ventricular dysfunction because relief of the obstruction can result in significant clinical and hemodynamic improvement. A more nuanced approach is required for patients with asymptomatic aortic stenosis in whom a recommendation for surgical intervention might be based on the functional assessment by exercise stress testing. Advanced age is associated with higher operative morbidity but is not a contraindication to surgical therapy. Balloon aortic valvuloplasty is a percutaneous technique in which a balloon catheter is positioned across the aortic valve. Inflation results in fracture or separation of the fused and calcified cusps. This procedure is most effective in young patients with noncalcified congenital aortic stenosis and is rarely used in adult patients with calcific aortic stenosis because of significant complications and a high restenosis rate (about 30% at 6 months). Medical interventions with cholesterol-lowering therapies to slow the progression of mild to moderate aortic stenosis are still under clinical inves-

0

B

0

1

2

3

6 7 8 4 5 Years since diagnosis

(35) 9

(34) 10

Figure 8-1 A, Natural history of aortic stenosis without surgical therapy. B, Natural history of mitral and aortic valve disease in an era when surgical therapy was not widely available. Survival rates in 42 patients with aortic stenosis (AS, orange circles with dotted line), 35 patients with aortic insufficiency (AI, orange circles with solid line), and 133 patients with mitral insufficiency (MI, yellow circles with solid line). Clinical course in AI, MS (red circles with dotted line), and MI is similar with a 5-year survival rate of about 80% and a 10-year survival rate of about 60%. Patients with AS have a worse prognosis, with 5- and 10-year survival rates of about 40% and 20%, respectively. (A from Ross J Jr, Braunwald E: Aortic stenosis. Circulation 38[Suppl V]:61, 1968. Copyright © 1968 American Heart Association. B from Rapaport E: Natural history of aortic and mitral valve disease, Am J Cardiol 35:221-227, 1975.)

tigation. Routine antibiotic prophylaxis is no longer recommended unless there is prior history of endocarditis.

Aortic Regurgitation Aortic regurgitation (AR) may be secondary to primary disease of the aortic leaflets, aortic root, or both (see Table 8-1). Abnormalities of the aortic leaflets may be secondary

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Table 8-2 Characteristic Physical, Electrocardiographic, and Chest Radiographic Findings in Chronic Acquired Valvular Heart Disease Physical Findings* Aortic stenosis

Aortic regurgitation

Mitral stenosis

Mitral regurgitation

Mitral valve prolapse

Tricuspid stenosis

Tricuspid regurgitation

Electrocardiogram

Radiograph

Pulsus parvus et tardus (may be absent in older patients or in patients with associated aortic regurgitation); carotid shudder (coarse thrill) Ejection murmur radiates to base of neck; peaks late in systole if stenosis is severe Sustained but not significantly displaced LV impulse A2 decreased, S2 single or paradoxically split S4 gallop, often palpable Increased pulse pressure Bifid carotid pulses Rapid pulse upstroke and collapse LV impulse hyperdynamic and displaced laterally Diastolic decrescendo murmur; duration related to severity Systolic flow murmur S3G common Loud S1 OS S2-OS interval inversely related to stenosis severity S1 not loud, and OS absent if valve heavily calcified Signs of pulmonary arterial hypertension

LV hypertrophy Left bundle branch block is also common Rare heart block from calcific involvement of conduction system

LV prominence without dilation Post-stenotic aortic root dilation Aortic valve calcification

LV hypertrophy, often with narrow deep Q waves

LV and aortic dilation

Left atrial abnormality Atrial fibrillation common RV hypertrophy pattern may develop if associated pulmonary arterial hypertension is present

Hyperdynamic LV impulse S3 Widely split S2 may occur Holosystolic apical murmur radiating to axilla (murmur may be atypical with acute mitral regurgitation, papillary muscle dysfunction, or mitral valve prolapse) One or more systolic clicks, often mid-systolic, followed by late systolic murmur Auscultatory findings dynamic Symptoms may include tall thin habitus, pectus excavatum, straight back syndrome Jugular venous distention with prominent α wave if sinus rhythm Tricuspid OS and diastolic rumble at left sternal border; may be overshadowed by concomitant mitral stenosis Tricuspid OS and rumble increased during inspiration Jugular venous distention with large regurgitant (systolic) wave Systolic murmur at left sternal border, increased with inspiration Diastolic flow rumble RV S3 increased with inspiration Hepatomegaly with systolic pulsation

LA abnormality LV hypertrophy Atrial fibrillation

Large LA: double-density, posterior displacement of esophagus, elevation of left main stem bronchus Straightening of left heart border as a result of enlarged left appendage Small or normal-sized LV Large pulmonary artery Pulmonary venous congestion Enlarged LA and LV Pulmonary venous congestion

Often normal Occasionally ST-segment depression and/or T-wave changes in inferior leads

Depends on degree of valve regurgitation and presence or absence of those abnormalities

Right atrial abnormality Atrial fibrillation common

Large RA

RA abnormality; findings are often related to cause of the tricuspid regurgitation

RA and RV are enlarged; findings are often related to cause of the tricuspid regurgitation

*Findings are influenced by the severity and chronicity of the valve disorder. LA, left atrium; LV, left ventricle; OS, opening snap; RA, right atrium; RV, right ventricle.

Chapter 8—Acquired Valvular Heart Disease to rheumatic disease, congenital abnormalities, endocarditis, or use of certain anorexigenic drugs. In addition, AR is commonly a consequence of degenerative and bicuspid aortic stenosis. An aortic root pathologic condition associated with annular and root dilation may result in separation or prolapse of the leaflets. With chronic AR, the left ventricle must accommodate the normal inflow from the left atrium in addition to the aortic regurgitant volume. As a result, the left ventricle dilates and hypertrophies to maintain normal effective forward flow and to minimize wall stress. As the AR progresses, these changes in left ventricular size and wall thickness may be insufficient to maintain normal left ventricular filling pressures, and irreversible myocyte damage may occur. As a result, the left ventricle will dilate further, and systolic function and effective stroke volume will decrease. Clinically, patients with chronic, severe AR may be asymptomatic for long periods secondary to the compensatory changes in the left ventricle. When symptoms do develop, they are primarily related to an elevation in left ventricular filling pressures and include dyspnea on exertion, orthopnea, and paroxysmal nocturnal dyspnea. Many patients will describe chest or head pounding secondary to the hyperdynamic circulation. If effective cardiac output is reduced, the patient may complain primarily of fatigue and weakness. As with aortic stenosis, angina may occur in patients with AR even in the absence of epicardial coronary artery disease secondary to elevated left ventricular filling pressures and reduced coronary perfusion pressure. On physical examination, patients with severe AR have a widened pulse pressure (difference between the systolic and diastolic pressures) as a result of the runoff of blood back into the left ventricle (see Table 8-2). The arterial pulse is usually bounding, with a rapid upstroke and quick collapse (Corrigan disease or water-hammer pulse) (see Chapter 4). The cardiac impulse is hyperdynamic and is displaced laterally and inferiorly. The murmur of AR is a high-pitched, decrescendo diastolic murmur best heard at the lower left sternal border with the patient sitting up and leaning forward. Asking the patient to hold his or her breath at end expiration while the hands are held behind the head may also improve the ability to auscultate the murmur of AR. A sys tolic ejection murmur is often heard secondary to increased forward flow across the aortic valve. An S3 gallop may be present, especially if the patient has developed symptoms of heart failure. A low-pitched, diastolic murmur (Austin Flint murmur) may be heard at the apex and confused with the murmur of mitral stenosis (MS). This sound is thought to be secondary to the incomplete opening of the mitral leaflets (functional MS) secondary to elevated left ventricular filling pressures or impingement of the AR jet on the anterior mitral leaflet. The natural history of chronic AR is varied. Many patients with moderate to severe AR will remain asymptomatic for many years and generally have a favorable prognosis. Other patients may have progression of AR severity and develop left ventricular dysfunction and symptoms of congestive heart failure. Echocardiography is the primary tool to monitor the progression of disease and optimize the timing of surgery. Prior studies have shown that patients at high risk are those with left ventricular end-systolic

87

diameters greater than 50 mm or an ejection fraction of less than 50%. Surgery is usually recommended before developing this degree of left ventricular enlargement or dysfunction. Therefore patients with known moderate to severe AR should be monitored regularly with noninvasive testing to detect early signs of cardiac (i.e., left ventricular) decompensation. Treatment of patients with moderate to severe AR theoretically should include vasodilator therapy, such as nifedipine or angiotensin-converting enzyme (ACE) inhi bitors, because these agents unload the left ventricle. Although some published data suggest that these agents may slow the progression of myocardial dysfunction and delay the need for surgery, more recent data do not support that contention. Valve replacement surgery should be considered in symptomatic patients and those with evidence of significant left ventricular enlargement or left ventricular systolic dysfunction. In patients with reduced left ventricular ejection fraction of short duration (14 months), valve replacement usually results in significant improvement in ventricular function. If left ventricular dysfunction has been present for a prolonged period, then permanent myocardial damage may occur. Although such patients should not be excluded from surgery, their long-term prognosis remains poor. As compared with chronic AR, acute AR is a medical emergency that often requires immediate surgical intervention. The causes of acute AR include infective endocarditis, traumatic rupture of the aortic leaflets, aortic root dissection, and acute dysfunction of a prosthetic valve. Acute AR is the result of hemodynamic instability because the left ventricle is unable to dilate to accommodate the increased diastolic volume, resulting in decreased effective forward flow. Left ventricular and left atrial pressures rise quickly, leading to pulmonary congestion. Patients with acute AR often exhibit symptoms and signs of cardiogenic shock. The patient is usually pale with cool extremities as a result of peripheral vasoconstriction. The pulse is weak and rapid, and the pulse pressure is normal or decreased. The murmur of acute AR is low pitched and short because of rapid equilibration of aortic and left ventricular pressures during diastole. An S3 gallop is often present. Echocardiography is useful to assess AR severity and to determine its cause and can be quickly performed at the bedside in the patient who is acutely ill. The medical treatment of acute AR includes vasodilator therapy and diuretics if the blood pressure is stable. In patients who are hemodynamically compromised, inotropic support and vasopressors may be necessary. For most patients with acute AR, urgent valve replacement remains the treatment of choice. Intra-aortic balloon counterpulsation is relatively contraindicated because it may worsen AR severity.

Mitral Stenosis MS occurs when thickening and immobility of the mitral leaflets impede flow from the left atrium to the left ventricle. Rheumatic fever is by far the most common cause of MS. Rarely, congenital abnormalities, connective tissue disorders, left atrial tumors, and overly aggressive surgical repair

88

Section III—Cardiovascular Disease Pulmonary congestion threshold

4 cm2

Flow

Mitral valve area 2 cm2

1 cm2

0.5 cm2 Pressure gradient Figure 8-2 Graphic illustration of the relationship between the diastolic gradient across the mitral valve and the flow through the mitral valve. As the mitral valve becomes more stenotic, the pressure gradient across the mitral valve must increase to maintain flow into the left ventricle. When the mitral valve area is 1 cm2 or less, the flow rate into the left ventricle cannot be significantly increased, despite a significantly elevated pressure gradient across the mitral valve. (Adapted from Wallace AG: Pathophysiology of cardiovascular disease. In Smith LH Jr, Thier SO [eds]: The International Textbook of Medicine, vol 1. Philadelphia, WB Saunders, 1981, p 1192.)

of a regurgitant valve may lead to obstruction of the mitral valve. Two thirds of patients with MS are women. The pathologic changes that occur with rheumatic MS include fusion of the leaflet commissures and thickening, fibrosis, and calcification of the mitral leaflets and chordae. These changes occur over many years before dysfunction becomes hemodynamically important. The initial hemodynamic change that occurs with MS is an elevated left atrial pressure created by obstruction to left ventricular inflow (Fig. 8-2). This pressure change is transmitted back to the pulmonary venous system and may result in pulmonary congestion. Initially, this change may only occur at more rapid heart rates, such as with exercise or atrial arrhythmias, when higher left atrial pressures develop during the shortened diastolic period. As the MS becomes more severe, left atrial pressure remains elevated even at normal heart rates, and symptoms related to elevated pulmonary venous pressures may be present at rest. Chronic elevations in pulmonary venous pressures may lead to an increase in pulmonary vascular resistance and pulmonary arterial pressures. If the MS is not corrected, irreversible changes in the pulmonary vasculature may occur, and signs and symptoms of right ventricular heart failure may develop. In contrast, left ventricular filling pressures are usually normal or low with mild to moderate MS. As the stenosis becomes severe, filling of the left ventricle is impaired, and stroke volume and cardiac output are reduced. Patients with MS of rheumatic origins usually develop symptoms during the third or fourth decade of life. Dyspnea, orthopnea, and atrial fibrillation are the most common symptoms. Some patients may have sudden hemoptysis secondary to rupture of the dilated bronchial veins (pulmonary apoplexy) or blood-tinged sputum associated with pulmonary edema. Peripheral embolism from left atrial thrombus

may also occur, even in the absence of atrial fibrillation. In long-standing, severe MS, patients may develop peripheral edema secondary to elevated right ventricular pressures and right ventricular dysfunction. Compression of the left recurrent laryngeal nerve from a severely dilated left atrium may result in hoarseness (Ortner syndrome). On physical examination, S1 is loud early in the course of MS because the leaflets remain fully open throughout diastole and then quickly close (see Table 8-2). As the leaflets become more calcified and immobile, S1 will become softer or completely absent. The opening snap is a high-pitched sound after the S2 and reflects the abrupt mitral valve opening. As the MS becomes more severe, the interval between the S2 and opening snap becomes shorter because left atrial pressure exceeds left ventricular pressure earlier in diastole. The characteristic low-pitched rumbling murmur of MS is best heard at the left ventricular apex with the patient in the left lateral decubitus position. The murmur is loudest in early diastole when rapid ventricular filling occurs. If sinus rhythm is present, the murmur may increase in intensity after atrial contraction (presystolic accentuation). In some patients, the murmur may only be heard at times of increased blood flow through the mitral valve, such as after exercise. If pulmonary artery pressures are elevated, a palpable P2 may be detected at the upper left sternal border. On auscultation, the pulmonic component of S2 is prominent and a right ventricular gallop may be present. Echocardiography is the most useful tool for pathologic assessment of the mitral apparatus as well as the severity of the stenosis. The characteristic rheumatic deformity observed with two-dimensional imaging is doming (i.e., hockey stick deformity) of the anterior mitral valve leaflet, which is secondary to fusion of the commissures and tethering of the leaflet tips (Fig. 8-3). In addition, the mobility of the leaflets

LV AMVL

PMVL

LA

Figure 8-3 Example of hockey stick deformity of mitral valve in chronic rheumatic heart disease as visualized by echocardiography. Tips of anterior mitral valve leaflet (AMVL) are tethered, thus restricting opening of the valve. Posterior mitral valve leaflet (PMVL) is thickened and has reduced mobility. Left atrium (LA) is characteristically enlarged.

Chapter 8—Acquired Valvular Heart Disease and the extent of valvular calcification can be assessed and used to determine treatment options. Doppler techniques allow calculation of the mitral valve area and the transvalvular gradient. Transesophageal echocardiography is a useful tool for studying the mitral apparatus and examining the left atrium for thrombus before percutaneous valvuloplasty. The severity of MS and associated hemodynamic changes can also be evaluated with cardiac catheterization. Measurements of the cardiac output and transvalvular gradient can be used to calculate the valve area by means of the Gorlin formula. A normal mitral valve area is 4 to 6 cm2, and critical MS is defined as a valve area less than 1 cm2. Patients with mild to moderate MS can usually be managed medically. Heart rate control is imperative in these patients because more rapid rates reduce the length of the diastolic filling period. This is especially true in patients with atrial fibrillation, in whom loss of atrial contraction may further reduce left ventricular filling. Anticoagulant therapy is indicated for patients with atrial fibrillation and for those with sinus rhythm who have had prior embolic events or who have moderate to severe MS. Diuretics are useful in relieving pulmonary congestion and signs of right ventricular heart failure. All patients should be instructed on the importance of endocarditis prophylaxis. Prophylaxis against recurrent bouts of rheumatic fever may be used in patients younger than 30 years. Patients with severe symptoms (New York Heart Association classes III through IV) and moderate to severe MS should be considered for a percutaneous or surgical intervention. Percutaneous balloon valvuloplasty is a new technique in which a balloon catheter positioned across the

89

mitral valve is quickly inflated, resulting in separation of the fused cusps. Optimal short- and long-term results are obtained in patients with pliable, noncalcified leaflets and chords, minimal mitral regurgitation (MR), and no evidence of left atrial thrombus. A surgical option in this same group of patients is open mitral valve commissurotomy. With direct visualization of the mitral valve, the surgeon is able to débride the valve, separate the fused cusps, and remove left atrial thrombi. Although the valve remains abnormal, this procedure is associated with a low operative mortality and a good hemodynamic result and may spare the patient from a valve replacement for many years. If mitral commissurotomy is not an option, valve replacement with a bioprosthetic or mechanical prosthesis can be performed.

Mitral Regurgitation MR can result from abnormalities of the mitral leaflets, annulus, chordae, or papillary muscles (see Table 8-1). The most common leaflet abnormality resulting in chronic MR is myxomatous degeneration of the mitral valves. This condition results in mitral valve prolapse (MVP), which progresses as the chordae become elongated or rupture (Fig. 8-4). Both acute and chronic rheumatic fever may also cause MR. With chronic MR, the left ventricle dilates to compensate for the increased regurgitant volume. However, in contrast to aortic insufficiency, the increased volume is ejected into the low-pressure left atrium. Thus, left ventricular wall stress and pressure remain normal for a significant period. If the left atrium dilates sufficiently to accommodate the increased

LV

LV

AMVL

PMVL

A

B

Figure 8-4 Typical example of mitral valve prolapse is visualized with transthoracic echocardiography. A, Prolapse of the posterior mitral valve leaflet (PMVL) behind the mitral valve annular plane results from lengthening and rupture of chordae tendineae. In this patient, a highly eccentric (blue) jet of moderate-to-severe mitral regurgitation is observed (B). AMVL, anterior mitral valve leaflet; LV, left ventricle.

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volume, left atrial and pulmonary venous pressures will remain normal. As the MR progresses, myocyte damage may occur, resulting in further left ventricular dilation, an elevation in diastolic filling pressures, and a reduction in left ventricular systolic function. As left atrial and pulmonary venous pressures increase, pulmonary congestion may occur. Patients with chronic compensated MR are usually asymptomatic and have normal functional capacity. When symptoms do occur, left ventricular systolic function is sometimes depressed. Patients may initially complain of fatigue and dyspnea with exertion secondary to reduced cardiac output and elevation in pulmonary venous pressures. If the MR remains untreated, pulmonary hypertension and right ventricular heart failure may occur. MR characteristically produces a holosystolic murmur best heard at the apex and radiating to the axilla and back (see Table 8-2). If an eccentric, anteriorly directed jet of MR is present, an ejection-quality murmur may be present and confused with an aortic outflow murmur. If the MR is secondary to MVP, a mid-systolic click may be present, followed by a late systolic murmur. MR associated with rheumatic mitral disease may be accompanied by heart sounds typical of MS. Echocardiography is the primary noninvasive method for defining mitral valve pathologic evaluation and assessing left ventricular size and function. Doppler techniques are useful in grading the severity of MR. Quantitative echocardiographic measures of MR severity are predictive of long-term survival, even in patients who are asymptomatic. Mitral valve repair appears to normalize the survival curves in this group of patients. MR can also be assessed during cardiac catheterization by estimating the amount of contrast medium that is ejected into the left atrium during left ventriculography. In addition, left ventricular size and systolic function can be quantitated, filling pressures can be measured, and the coronary anatomy can be defined. The medical treatment of patients with compensated chronic MR is afterload reduction with vasodilator therapy, such as ACE inhibitors or hydralazine. The timing of surgery is difficult because the development of symptoms often indicates the presence of left ventricular dysfunction and irreversible myocardial damage. In addition, mitral valve replacement with disruption of the chordal apparatus often results in further left ventricular dilation and decline in systolic function. Echocardiographic parameters that identify patients at risk for a poor response to mitral valve replacement are a left ventricular end-diastolic diameter greater than 70 mm, an end-systolic diameter greater than 45 mm, and a low-normal or reduced left ventricular ejection fraction. Patients with known MR should be followed with yearly studies to monitor left ventricular function and size so that surgery can be performed before irreversible myocyte damage and left ventricular remodeling occur. The development of either atrial fibrillation or pulmonary hypertension may be an indication for earlier surgical intervention, even if left ventricle size and function are still normal. In many patients, the mitral valve may be repaired, thus avoiding many of the potential complications associated with valve replacement. With this surgery, sections of redundant leaflet can be excised, leaflets débrided, and chordae

shortened. A prosthetic ring (annuloplasty) can be sewn into the mitral annulus to reduce the size of the orifice and increase the degree of leaflet coaptation. The advantage of this procedure is that preservation of the mitral apparatus helps maintain normal left ventricular geometry and function. In addition, long-term anticoagulation is not necessary in most patients in sinus rhythm. Valve repair is generally not indicated if the mitral valve is heavily calcified or disrupted secondary to papillary muscle disease or endocarditis. In these instances, valve replacement is the procedure of choice. Based on excellent surgical outcomes and long-term durability, mitral valve repair is the procedure of choice in all patients in whom it is technically feasible. Severe MR, even in the absence of symptoms or left ventricular dysfunction, may be an appropriate reason for surgical intervention. A variety of percutaneous mitral valve repair techniques are in development. Acute severe MR is often a life-threatening condition that can result from a variety of papillary muscle, chordal, and leaflet abnormalities (see Table 8-1). Patients with acute MR usually become severely ill because the left atrium does not dilate to accommodate the regurgitant volume. As a result, left atrial and pulmonary venous pressures abruptly increase, resulting in pulmonary congestion. In addition, the decreases in stroke volume and cardiac output result in an increase in systemic vascular resistance and, as a consequence, an increase in the severity of MR. Patients usually exhibit pulmonary edema and signs of cardiogenic shock. On auscultation, the MR murmur is often a soft, low-pitched sound in early systole, resulting from rapid equilibration of left ventricular and left atrial pressures. Afterload reduction with either an intravenous vasodilator, such as nitroprusside, or an intra-aortic balloon pump may help stabilize the patient before urgent valve replacement surgery. Ischemia of the posterior wall or papillary muscles may cause acute but transient MR.

Mitral Valve Prolapse MVP is reported to be present in about 1% to 3% of the population. Although MVP can be observed in all ages and in both sexes, epidemiologic studies suggest that the prevalence is greater in women than it is in men. In some patients, MVP is inherited as an autosomal dominant trait with variable penetrance. MVP is present when superior displacement in ventricular systole of one or both mitral valve leaflets exists across the plane of the mitral annulus toward the left atrium (see Fig. 8-4). Primary or classic MVP occurs when myxomatous degeneration of the mitral valve occurs without evidence of systemic disease. Secondary MVP is also characterized by myxomatous degeneration of the mitral apparatus but in the presence of a recognizable systemic or connective tissue disease, such as Marfan syndrome or systemic lupus erythematosus. Functional MVP results from structural abnormalities of the mitral annulus or papillary muscles or reduced left ventricular volume, but the mitral leaflets are anatomically normal. Most patients with MVP are asymptomatic. Although a variety of nonspecific symptoms have been associated with

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MVP (e.g., chest pain, palpitations, dizziness, anxiety [MVP syndrome]), the frequency of these symptoms is no different from that in the general population. MVP may be associated with varying degrees of MR. MR severity is probably the main determinant of long-term complications. The characteristic physical examination finding in MVP is the midsystolic click, followed by a late systolic murmur (see Table 8-2). The auscultatory findings of MVP are subtle and are greatly affected by changes in left ventricular volume. Maneuvers that reduce left ventricular volume will result in prolapse of the redundant leaflets early in systole; as a result, the click will occur early in systole, and the MR murmur will sound more holosystolic. If left ventricular volume is increased, the click will be heard late in systole, followed by a short systolic murmur. The diagnosis of MVP is usually confirmed by echocardiography, which allows examination of the mitral apparatus and determination of the MR severity. Most patients with mild prolapse and insignificant MR are asymptomatic and require no specific intervention. Endocarditis prophylaxis is generally recommended only if mild or greater MR exists. However, in some individuals, the MR may progress to such a degree that serial examinations and echocardiograms are necessary to monitor MR severity and left ventricular function. Middle-aged and older men and patients with asymmetrical prolapse are at highest risk for developing complications from MVP, such as severe MR and endocarditis. MR that acutely worsens may be related to rupture of the chordae tendineae. Sudden death in the absence of hemodynamically significant MR is rare. Patients with MVP and evidence of structural leaflet abnormalities or significant MR should receive endocarditis prophylaxis. Symptomatic arrhythmias should be treated as discussed in Chapter 10. For patients with severe MR, mitral valve repair or replacement may be indicated as discussed earlier (see “Mitral Regurgitation”).

is a low-pressure system, the mean gradient across the tricuspid valve may be quite small (5 mm Hg) yet still clinically important.

Tricuspid Stenosis

Pulmonic stenosis is most often congenital in origin and is discussed further in Chapter 7. Rheumatic deformity of the pulmonic valve is rare and not usually associated with hemodynamically important obstruction. Pulmonic regurgitation is most often the result of dilation of the annulus secondary to pulmonary hypertension of any cause. Symptoms are usually related to the primary disease and in most cases are secondary to right ventricular heart failure. In this setting, the murmur of pulmonic regurgitation is a high-pitched, blowing murmur best heard at the second left intercostal space (Graham Steell murmur). In the absence of pulmonary hypertension, the murmur is usually low pitched and occurs late in diastole. Treatment is usually directed at the underlying cause of the pulmonary hypertension. Rarely and usually in the setting of congenital or previously repaired pulmonic valve disease, the valve will need to be replaced because of intractable right ventricular heart failure.

Tricuspid stenosis is most often rheumatic in origin and is usually associated with mitral or aortic disease. Other rare causes include carcinoid syndrome, congenital valve abnormalities, and leaflet tumors or vegetations. Similar to MS, tricuspid stenosis is more common in women than it is in men and tends to be a slowly progressive disease. Patients generally exhibit symptoms and signs of right ventricular heart failure, such as fatigue, abdominal bloating, and peripheral edema. On physical examination, a prominent jugular venous a wave may be present if the patient is in sinus rhythm and may be confused with an arterial pulsation. In addition, a palpable presystolic pulsation coinciding with atrial contraction may be felt on palpation of the liver. On auscultation, the findings of tricuspid stenosis may not be detected secondary to the presence of mitral and aortic valve disease. However, an opening snap may be audible at the left sternal border, followed by a soft, high-pitched diastolic murmur. In contrast to MS, the murmur of tricuspid stenosis is shorter in duration and accentuated with inspiration. Tricuspid stenosis can be diagnosed by echocardiography or right ventricular catheterization. Because the right heart

Tricuspid Regurgitation Tricuspid regurgitation (TR) is most often secondary to dilation of the right ventricle and tricuspid annulus that may occur with right ventricular heart failure of any cause. Other causes include endocarditis, carcinoid syndrome, congenital abnormalities, and chest wall trauma. In the absence of pulmonary hypertension, TR is usually well tolerated. However, if right ventricular dysfunction is present, patients usually have symptoms of right ventricular heart failure. On physical examination, the jugular veins are distended, and a prominent v wave is usually present. Hepatic congestion is common and often associated with a palpable systolic pulsation. The murmur of TR is high pitched and pansystolic and is best heard along the sternal border. Maneuvers that increase venous return, such as inspiration or leg raising, accentuate the murmur and are helpful in differentiating TR from MR or aortic outflow tract murmurs. If the TR is acute, the murmur is usually soft and present only during early systole. TR related to pulmonary hypertension and right ven tricular dysfunction will usually significantly improve with treatment of the underlying cause. Repair of the tricuspid annulus (annuloplasty) may restore tricuspid valve com petence in patients with persistent symptoms despite treatment. In individuals with a primary leaflet pathologic condition, tricuspid valve replacement may be necessary.

Pulmonic Stenosis and Regurgitation

Multivalvular Disease Multivalvular disease is common, especially in patients with rheumatic heart disease and in the older adult population.

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Often, regurgitant lesions, such as TR and pulmonic regurgitation, are the result of another valve lesion, such as MS in association with pulmonary hypertension. In general, symptoms are most often related to the most proximal valve lesion. However, the severity of each individual lesion may be difficult to assess clinically, and, therefore, careful evaluation with echocardiography and right and left ventricular heart catheterization is necessary to assess valve function before any planned surgery. Failure to correct all significant valvular lesions may result in a poor clinical outcome. Double valve replacement is associated with a higher operative and long-term mortality than single valve replacement.

Rheumatic Heart Disease Acute rheumatic fever (ARF) is the sequelae of group A β-hemolytic streptococcal infection. The disease is thought to be secondary to an abnormal immunologic response to the streptococcal infection. ARF usually occurs in children 4 to 9 years of age, with boys and girls being equally affected. Although the prevalence of this disease has significantly decreased in the United States over the past several decades, it still poses a major health care problem in many developing nations, and endemic outbreaks have been identified even in the United States. ARF is characterized by a diffuse inflammation of the heart (pancarditis). An exudative pericarditis is common and often results in fibrosis and obliteration of the pericardial sac. Constrictive pericarditis is rare. The myocardium is often infiltrated with lymphocytes, and areas of necrosis may occur. The characteristic histologic finding in the myocardium is the Aschoff body, which is a confluence of monocytes and macrophages surrounded by fibrous tissue. Valvulitis is characterized by verrucous lesions on the leaflet edge, which are composed of cellular infiltrates and fibrin. The mitral valve is most frequently involved, followed by the aortic valve. Involvement of the tricuspid or pulmonic valve is rare. Valvulitis can be recognized by the presence of a new insufficiency murmur. Aortic stenosis and MS do not occur for many years, when progression of the fibrosis results in restricted leaflet mobility. The presentation of ARF is usually an acute, febrile illness 2 to 4 weeks after a streptococcal pharyngitis infection. Because the diagnosis of ARF cannot be made by laboratory tests alone, guidelines based on the symptoms and a physical examination have been established (modified Jones criteria) (Table 8-3). A diagnosis of ARF can be made Table 8-3 Revised Jones Criteria Major Criteria Carditis (pleuritic chest pain, friction rub, heart failure) Polyarthritis Chorea Erythema marginatum Subcutaneous nodules Minor Criteria Fever Arthralgia Previous rheumatic fever or known rheumatic heart disease

if two major, or one major and two minor, criteria are present after a recent, documented streptococcal pharyngitis infection. Major criteria include evidence of carditis (e.g., pleuritic chest pain, friction rub, heart failure, MR), poly arthritis, chorea, erythema marginatum, and subcutaneous nodules. Minor criteria include fever, arthralgia, and a history of rheumatic fever or known rheumatic heart disease. Once the diagnosis is established, a course of therapy with penicillin is indicated to eradicate the streptococcal infection. Salicylates are effective for the treatment of fever and arthritis. Corticosteroids and immunosuppressive therapy have not been proved beneficial in the management of the carditis. Heart failure should be treated with standard therapy. Recurrent attacks of rheumatic fever are common, especially during the first 5 to 10 years after the primary illness. Rheumatic fever prophylaxis should be continued during this period, and for 10 years in patients with a high exposure rate to streptococcal infection (e.g., health care professionals, child care workers, military recruits). Patients with significant rheumatic heart disease should receive prophylaxis indefinitely, considering the high rate of recurrence in these individuals. The recommended therapy for prophylaxis is an intramuscular injection of 1.2 million units of benzathine penicillin monthly. Alternatively, oral penicillin or erythromycin may be used. Noncompliance with these agents reduces the effectiveness of this mode of therapy.

Prosthetic Heart Valves Two types of artificial heart valves are available: mechanical valves (tilting disk and bi-leaflet) and tissue valves (bioprostheses) (Fig. 8-5). The mechanical valves have a favorable

Caged ball

Caged disk

Bi-leaflet tilting disk Tilting disk Tissue Figure 8-5 Designs and flow patterns of major categories of prosthetic heart valves: caged ball, caged disk, tilting disk, bi-leaflet tilting disk, and bioprosthetic (tissue) valves. Whereas flow in mechanical valves must course along both sides of the occluder, bioprostheses have a central flow pattern. (From Schoen FJ, Titus JL, Lawrie GM: Bioengineering aspects of heart valve replacement. Ann Biomed Eng 10:97-128, 1982; Schoen FJ: Pathology of cardiac valve replacement. In Morse D, Steiner RM, Fernandez J [eds]: Guide to Prosthetic Cardiac Valves. New York, Springer-Verlag, 1985, p 208.Copyright © 1985 Springer-Verlag.)

Chapter 8—Acquired Valvular Heart Disease hemodynamic profile and are extremely durable. However, mechanical valves carry a high thromboembolic risk and require long-term anticoagulation. Bioprosthetic use is less likely to be complicated by thromboembolic disease, but the durability of the valve is significantly less than with mechanical valves, especially in young patients. The type of prosthesis used in a particular patient is dependent on multiple factors, including the patient’s age, suitability for long-term anticoagulation, and valve position. The American College of Cardiology/American Heart Association guidelines are available for anticoagulation therapy in patients with prosthetic heart valves. All patients with mechanical valves require warfarin therapy. Aspirin (75 to 100 mg/day) is recommended as sole long-term therapy in patients with biologic prosthetic valves and in combination with warfarin in patients with mechanical valves. Warfarin is recommended during the first 3 months after surgery in patients receiving biologic prostheses. The INR should be maintained at 2.3 to 3 in low-risk patients with mechanical aortic valves. High-risk features (e.g., atrial fibrillation, left ventricular dysfunction, previous thromboembolism, and hypercoagulable state) should lead to an INR goal of 2.5 to 3.5 in patients with mechanical AVR. The INR should be maintained at 2.5 to 3.5 in all patients with mechanical mitral valves. Replacement of a diseased valve with an artificial valve results in a new set of potential risks and complications with the prosthesis. All valve prostheses result in some degree of stenosis because the effective valve orifice is smaller than that of the native valve. Thrombosis or calcification of the prosthetic valve can result in prosthetic dysfunction and hemodynamically important stenosis. Prosthetic valve insufficiency can result from perivalvular leaks in the area of the sewing ring. With bioprosthetic valves, deterioration of the prosthetic valve leaflets can lead to valve insufficiency and stenosis. Hemolysis is a frequent complication of the older mechanical valves (e.g., ball cage, disk cage) and can occur with present-day prostheses if turbulent flow asso ciated with prosthetic valve dysfunction exists, especially regurgitation. Endocarditis remains a potential complication in all patients with prosthetic valves. The guidelines for endocarditis prophylaxis are provided later (see “Endocarditis Prophylaxis”). Evaluation of prosthetic valve function is best performed with two-dimensional and Doppler echocardiographic techniques. Transesophageal echocardiography is particularly useful in studying prosthetic valves when thrombosis or endocarditis is suggested. Mechanical valves can be assessed with fluoroscopy to determine whether leaflet excursion is normal. Gated cardiac computed tomography may also be helpful (Fig 8-6; Web Fig 8-1).

Endocarditis Prophylaxis Patients with valvular heart disease and prosthetic heart valves are at increased risk for developing endocarditis (Table 8-4) (see Chapter 100). In the past, endocarditis prophylaxis was widely recommended for abnormal valves. However, recently updated guidelines reflect the fact that only an extremely small number of cases of infective endocarditis may be prevented by antibiotic prophylaxis, even if it were 100% effective. Infective endocarditis is more likely

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A

B

C Figure 8-6 Images of mechanical heart valves obtained with gated cardiac CT. Maximum intensity projection of bileaflet tilting disk mechanical aortic prosthesis in closed (A) and open (B) positions. Dynamic images of this valve can be seen on Web Figure 8-1. (C) Volume-rendered image showing closed, single-leaflet aortic valve and open bi-leaflet tilting disk mitral valve in diastole. Both valves were clearly seen to open and close normally on the dynamic line images. This patient had suspected prosthetic valve dysfunction that was incompletely evaluated by both fluoroscopy and transesophageal echocardiography.

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Table 8-4 Cardiac Conditions in which Antibiotic Prophylaxis Is Recommended Prosthetic heart valves Previous bacterial endocarditis Congenital cardiac malformations (class IIa) Unrepaired cyanotic Repaired with residual shunt First 6 months after repair with prosthetic material Cardiac transplant recipients with valve regurgitation due to structurally abnormal valve

Table 8-5 Dental and Surgical Procedures in which Endocarditis Prophylaxis Is Recommended For patients with the underlying cardiac conditions shown in Table 8-4, prophylaxis is reasonable for all dental procedures that involve manipulation of either gingival tissue or the periapical region of teeth or perforation of oral mucosa. Prophylaxis is not recommended solely on the basis of an increased lifetime risk for acquisition of infective endocarditis. Administration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary or gastrointestinal tract procedure.

to result from frequent exposure to random bacteremia associated with daily activities than from bacteremia caused by a dental, gastrointestinal tract, or genitourinary procedure. Lastly, the risk for antibiotic-associated adverse events exceeds the benefit (if any) of prophylactic therapy. The role of antibiotic prophylaxis is to prevent infection of the abnormal valve during procedures that are associated with transient bacteremia (Table 8-5). The flora commonly found in the part of the body being instrumented determines the choice of antibiotics. All patients with known valve disease or prosthetic heart valves should carry a card indicating the nature of their valve lesion and the type of endocarditis prophylaxis recommended. The Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the American Heart Association does not recommend routine antibiotic prophylaxis in patients with valvular heart disease undergoing uncomplicated vaginal delivery or caesarean section unless infection is suspected. Antibiotics are optional for high-risk patients with prosthetic heart valves, a previous history of endocarditis, complex congenital heart disease, or a surgically constructed systemic-pulmonary conduit.

Prospectus for the Future Infectious disease such as ARF as the principal cause of acquired valvular heart disease will continue to decline worldwide. For isolated mitral valvular stenosis, for example, percutaneous approaches by a skilled operator will become the standard and the preferred treatment modality over a surgical procedure. Aortic and mitral regurgitation caused by degenerative and

References American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease. J Am Coll Cardiol 32:el-e142, 2008. Freed LA, Levy D, Levine RA, et al: Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med 341:1-7, 1999. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, et al: Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med 352:875-883, 2005.

other acquired diseases will create the major morbidity and mortality rates with advancing age. In the next decade, rapid advances in percutaneous approaches to address mitral regurgitation and aortic stenosis may radically change our practice and strategies for treating these conditions.

Freeman RV, Otto CM: Spectrum of calcific aortic valve disease: Pathogenesis, disease progression, and treatment strategies. Circulation 111:3316-3326, 2005. Zoghbi WA, Enriquez-Sarano M, Foster E, et al: Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 16:777-802, 2003. ACC/AHA guidelines update on valvular heart disease: focused update on infective endocarditis. J Am Coll Cardiol 52:676-685, 2008.

Chapter

9

III

Coronary Heart Disease Andrew D. Michaels

Epidemiology Coronary heart disease (CHD) is the leading cause of death in the industrialized world. Apart from its influence on mortality, it causes substantial morbidity, disability, and loss of productivity. With improvements in diagnosis, prevention, and treatment, the mortality rate from CHD has declined gradually over the past several decades. Nonetheless, 1.2 million people have a myocardial infarction (MI) or fatal cardiac event each year in the United States alone. Nearly half of all deaths in industrialized nations and 25% of those in developing countries are due to CHD. By the year 2020, CHD is predicted to surpass infectious disease as the world’s leading cause of death and disability.

Pathophysiology of Atherosclerosis In the industrialized world, atherosclerosis often begins in the early decades of life. One in six American teenagers dying accidentally has pathologic evidence of coronary atherosclerosis. Several processes contribute to the initiation and progression of atherosclerosis, including accumulation of lipoproteins, endothelial injury, and inflammation. In the early phase of atherosclerosis, small lipoprotein particles penetrate the vascular endothelium, where they are oxidized and coalesce into aggregates in the intimal layer. This process is accelerated at sites of endothelial injury, which may be caused or accelerated by systemic hypertension, hypercholesterolemia, cigarette smoking, or excessive sheer forces. The accumulation of intimal lipid aggregates stimulates the expression of adhesion molecules (e.g., intracellular adhesion molecule-1, vascular cell adhesion molecule-1, selectins) on the luminal surface of the endothelial cells, thereby enabling them to bind circulating monocytes (e.g., macrophages). The adherent monocytes intercalate between the endothelial cells into the intimal layer in response to chemokines and cytokines produced by endothelial and medial smooth muscle cells. The intimal monocytes

ingest the lipoprotein aggregates to become lipid-filled monocytes, or foam cells. Aggregates of these foam cells make up the earliest visible evidence of atherosclerosis, or the fatty streak. Foam cells replicate and release proinflammatory mediators, thereby perpetuating the local inflammatory process with resultant lesion progression. In addition, they release enzymes that cause endothelial denudation. Because the endothelium is involved in the control of vascular tone through its production of vasodilating substances such as prostacyclin and nitric oxide (e.g., endothelium-derived relaxing factor) and thrombosis, injury to these cells impairs vasodilation and creates a local prothrombotic state. Circulating platelets adhere to sites of endothelial injury and release growth factors, which stimulate the migration and proliferation of smooth muscle cells and fibroblasts from the media. This leads to formation of a fibrous cap over the lipid-rich core (Web video 1—Coronary Atherosclerosis, http://www.heartsite.com/html/cad.html). As lipids continue to accumulate in the foam cells, they undergo necrosis and leave a remnant lipid pool in the core of the plaque. Metalloproteinase enzymes (e.g., collagenase, gelatinase) released by macrophages and mast cells in the plaque degrade collagen and extracellular matrix proteins adjacent to the lipid pool, whereas cytokines (e.g., interferon-α) released by T lymphocytes inhibit the formation of collagen by vascular smooth muscle cells. This combination of increased collagen degradation and decreased collagen production creates a vulnerable plaque, which is predisposed to fissure or rupture. Such vulnerable plaques have a lipid-laden core and a thin, weakened fibrous cap. When the thin fibrous cap fissures or ruptures, highly thrombogenic collagen and lipid are exposed to circulating blood with resultant adhesion of platelets and formation of an intraluminal thrombus. Activated platelets release substances (e.g., thromboxane, serotonin) that promote vasoconstriction and thrombus propagation. When the extent of platelet aggregation and thrombosis is sufficient to impair blood flow (partially or completely), an acute coronary event (unstable angina, non–ST-segment elevation myocardial infarction [NSTEMI] or ST-segment elevation myocardial infarction [STEMI]) occurs. 95

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Figure 9-1 Angiograms of the right coronary artery. A, Discrete stenosis is observed in the middle segment of the artery (arrow). B, Same artery is shown after successful balloon angioplasty of the stenosis and placement of an intracoronary stent.

When the atherosclerotic plaque is covered with a thick fibrous cap, rupture is less likely, but the plaque may gradually increase in size. As plaque volume increases, the coronary arterial lumen is compromised, and blood flow is impaired (Fig. 9-1). The hemodynamic significance of plaque is determined by the length and severity of the luminal narrowing; in general, a 70% decrease in the luminal diameter of a coronary artery limits blood flow in the presence of increased myocardial oxygen demands (e.g., exercise, emotional excitement), leading to the clinical condition of exertional angina. A 90% decrease in luminal diameter is sufficient to limit flow even when myocardial oxygen demands are normal. For intermediate-severity lesions with a diameter stenosis between 40% and 70%, assessing the hemodynamic significance of the stenosis with either fractional flow reserve (FFR; ratio of the mean coronary pressure distal to the stenosis [acquired by a micromanometer pressure transducer on a coronary angioplasty guidewire] divided by the mean arterial pressure proximal to the stenosis) or stress testing may help determine the requirement for coronary revascularization.

Table 9-1 Risk Factors and Markers for Coronary Artery Disease Nonmodifiable Risk Factors Age Male sex Family history of premature coronary artery disease Modifiable Independent Risk Factors Hyperlipidemia Hypertension Diabetes mellitus Metabolic syndrome Cigarette smoking Obesity Sedentary lifestyle Heavy alcohol intake Markers Elevated lipoprotein(a) Hyperhomocysteinemia Elevated high-sensitivity C-reactive protein (hsCRP) Coronary arterial calcification detected by electron-beam computed tomography (EBCT) or multidetector computed tomography (MDCT)

Risk Factors Several risk factors for the development of atherosclerosis have been identified (Table 9-1). Nonmodifiable risk factors include (1) advanced age, (2) male sex, and (3) family history of premature atherosclerosis. The prevalence of coronary artery disease (CAD) increases with age. At any given age, the prevalence is higher in men than in women. On average, the clinical manifestations of CAD become evident about 10 years later in women than in men. A family history of premature atherosclerosis (occurring in men before age 55 years and in women before age 65 years) increases the risk for atherosclerosis in an individual, likely as a result of environ-

mental factors (e.g., dietary habits, cigarette smoking) and a genetic predisposition to the disease. Other risk factors are modifiable, and their treatment may decrease the risk for atherosclerosis. These modifiable risk factors include hyperlipidemia, hypertension, diabetes mellitus, metabolic syndrome, cigarette smoking, obesity, sedentary lifestyle, and excessive alcohol intake. Although several definitions of the metabolic syndrome have been endorsed, the definition adopted by the National Cholesterol Education Program Adult Treatment Panel requires at least three of the following five criteria: waist circumference

Chapter 9—Coronary Heart Disease more than 102 cm in men and more than 88 cm in women; triglyceride level 150 mg/dL or higher; high-density lipoprotein (HDL) cholesterol level lower than 40 mg/dL in men and lower than 50 mg/dL in women; blood pressure 130/85 mm Hg or higher; and serum glucose 110 mg/dL or higher. Using these criteria, nearly 25% of the U.S. population has metabolic syndrome. Finally, markers associated with an increased incidence of CAD include lipoprotein(a), hyperhomocysteinemia, high-sensitivity C-reactive protein (hsCRP), and coronary arterial calcification. Lipids play a central role in the atherosclerotic process, and elevated levels of cholesterol, primarily low-density lipoprotein (LDL) cholesterol, are associated with accelerated atherosclerosis (Web video 1—Coronary Atherosclerosis, http://www.heartsite.com/html/cad.html). HDL cholesterol, by contrast, functions as a protective agent, and its serum level is inversely related to the risk of CAD. Elevated triglycerides are often associated with reduced levels of HDL cholesterol and are an independent risk factor for CAD. Large trials of lipid-lowering therapy have demonstrated the effectiveness of cholesterol reduction in the primary and secondary prevention of CAD. Systemic hypertension, defined as a systolic arterial pressure greater than 140 mm Hg or a diastolic pressure greater than 90 mm Hg, increases the risk for CAD. The risk increases proportionally with the extent of blood pressure elevation, and proper treatment of hypertension reduces the risk. Diabetes mellitus increases both the risk for developing CAD and the mortality associated with it. Although CAD is the leading cause of death in adult patients with diabetes, tight glycemic control has not been shown to reduce the risk. Diabetes mellitus often co-exists with other risk factors, including dyslipidemia (elevated triglyceride level, low HDL level), hypertension, and obesity. This grouping of risk factors has been termed the metabolic syndrome, and its presence identifies a person at increased risk for having or developing atherosclerotic disease. Cigarette smoking has adverse effects on the lipid profile, clotting factors, and platelet function and is associated with a twofold to threefold increase in the risk for CAD. Cessation of smoking reduces the excess risk for a coronary event by 50% within the first 1 to 2 years of quitting. Obesity, defined as a body mass index greater than 30 kg/m2, is often associated with other risk factors (e.g., hypertension, dyslipidemia, glucose intolerance); in addition, obesity appears to be an independent risk factor for CAD. The distribution of body fat is important, with abdominal adiposity posing a substantially greater risk for CAD in both men and women. Multiple observational studies have demonstrated an inverse relationship between the amount of physical activity and the risk for CAD. Although the ideal duration, frequency, and intensity of such physical activity have not been determined, numerous studies have shown that exercise is beneficial in healthy patients and those with or at risk for CAD. Moderate alcohol intake (1 to 2 drinks daily) is associated with a reduction in the risk for cardiovascular events; in contrast, heavy alcohol intake increases cardiovascular mortality. Lipoprotein(a) consists of LDL cholesterol linked to an apo(a) molecule. It has a homologic structure with plas-

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minogen and interferes with the generation of plasmin, thereby creating a predisposition to thrombosis. Elevated levels of homocysteine are associated with an increased risk for coronary, cerebral, and peripheral vascular disease. Hyperhomocysteinemia can be treated effectively with dietary folate supplementation. However, such treatments have not been shown to reduce the incidence of stroke or cardiovascular events in patients with elevated serum homocysteine levels. CRP, a marker of inflammation, may indicate or contri bute to an increased propensity for plaque rupture and thrombosis. Elevated serum CRP levels—when measured with the new high-sensitivity assays (i.e., hsCRP)—strongly correlate with the risks for MI, stroke, peripheral arterial disease, and sudden cardiac death. Levels of hsCRP lower than 1 mg/L are associated with a low risk for vascular events; levels of 1 to 3 mg/L pose an intermediate risk; levels greater than 3 mg/L create a high risk. In healthy patients without hyperlipidemia but with an hsCRP greater than 2 mg/L, statin therapy has been shown to reduce the risk for myocardial infarction, stroke, revascularization for unstable angina, and death from cardiovas cular causes. Coronary arterial calcification is a prominent feature of coronary atherosclerosis, and it correlates with the presence and severity of CAD. Electron-beam computed tomography (EBCT) or multidetector computed tomography (MDCT) can accurately quantify coronary calcification, thereby serving as screening tests for CAD in asymptomatic patients. Currently, the usefulness of EBCT or MDCT and hsCRP in the clinical setting is poorly defined. However, the finding of coronary calcification in patients without known CAD or risk factors for CAD may identify those who warrant aggressive risk factor modification.

Nonatherosclerotic Causes of Cardiac Ischemia Although atherosclerosis is the most common disease affecting the coronary arteries, several nonatherosclerotic processes may produce myocardial ischemia or MI. Embolization from infective endocarditis, mural thrombi in the left atrium or ventricle, prosthetic valves, intracardiac tumors, or paradoxical emboli from the venous system across an atrial or a ventricular septal defect or pulmonary arteriovenous malformation may compromise coronary blood flow, leading to myocardial ischemia or MI. Chest wall trauma may result in coronary arterial dissection or thrombosis. Aortic dissection can propagate to the aortic root and occlude a coronary artery at its origin. Coronary arterial dissection may occur spontaneously during pregnancy or with connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome. Several forms of arteritis may involve the coronary arteries, including syphilis, Takayasu arteritis, polyarteritis nodosa, systemic lupus erythematosus, and giant cell arteritis. These syndromes may result in obstruction, occlusion, or thrombosis of the coronary arteries. Kawasaki disease, a

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mucocutaneous lymph node syndrome, is a systemic disease of children that causes coronary vasculitis with resultant coronary aneurysms. Spontaneous in situ coronary thrombosis may occur in the setting of hematologic disorders (e.g., polycythemia vera, essential thrombocytosis, disseminated intravascular coagulation, sickle cell anemia, paroxysmal nocturnal hemoglobinuria). Congenital coronary anomalies may cause myocardial ischemia. Spontaneous coronary spasm (e.g., Prinzmetal vasospastic angina) with or without underlying CAD may cause myocardial ischemia or, rarely, MI. Cocaine use may result in myocardial ischemia or MI through several mechanisms, including coronary vasospasm, thrombosis, and accelerated atherosclerosis. An occasional patient treated with sumatriptan for migraine headaches or paclitaxel for cancer may experience MI in the absence of CAD. In 10% to 20% of patients with suggested angina, coronary angiography reveals normal epicardial coronary arteries. In some of these individuals, microvascular or small vessel disease, the syndrome X, has been implicated. Studies have suggested that women have a higher prevalence of syndrome X compared with men presenting with possible acute coronary syndrome. The small resistance vessels in these patients, which are not visualized angiographically, have reduced vasodilatory capability. This dysfunction may lead to myocardial ischemia, as evidenced by exercise-related abnormalities on echocardiographic or nuclear scintigraphic studies. Some patients respond to treatment with common anti-anginal medications; although, in general, these drugs are less effective in patients with syndrome X than in those with atherosclerotic CAD. Finally, myocardial ischemia may result when significant increases in the demand for myocardial oxygen exceed oxygen supply. Such an oxygen supply-demand imbalance may occur in individuals with thyrotoxicosis, aortic stenosis, aortic insufficiency, tachyarrhythmia, or sepsis. Diminished oxygen supply may occur as a result of acute blood loss, hypotension, severe anemia, or carbon monoxide poisoning.

Endothelial dysfunction secondary to atherosclerosis impairs the ability of the coronary arterioles to dilate when oxygen demands increase. In addition, when a flow-limiting stenosis is present in an epicardial coronary artery, the arterioles distal to the stenosis may already be maximally or nearly maximally dilated in the resting state. The inability of the arterioles to dilate and increase coronary arterial flow during periods of increased demand (e.g., decreased coronary vasodilator reserve) results in a supply-demand mismatch, with resultant ischemia and the clinical pattern of stable angina. When myocardial oxygen supply cannot meet oxygen demand, myocardial ischemia occurs. This ischemia, in turn, initiates a series of pathophysiologic events. Regional myocardial hypoxia causes anaerobic glycolysis, lactate production, intracellular acidosis, and disordered calcium homeostasis. These intracellular changes induce abnormalities in myocardial relaxation, leading to reduced compliance and contraction, which cause regional wall motion abnormalities. Finally, electrocardiographic (ECG) evidence of ischemia (i.e., ST-segment depression or elevation) occurs, and angina pectoris ensues. If myocardial ischemia is transient, the duration of the resultant mechanical dysfunction may be short. In contrast, more prolonged ischemia may produce myocardial stunning, hibernation, or even an MI. Myocardial stunning refers to a prolonged period (e.g., hours, days) of reversible myocardial dysfunction after an ischemic event. Hibernation occurs in the setting of chronic ischemia when oxygen delivery is adequate to maintain myocardial viability but inadequate to maintain normal function. The clinical importance of the hibernating state is that restoration of blood flow to the involved myocardium results in improved mechanical function. Because of limited energy expenditure, conduction tissue is more resistant to ischemia than contractile tissue. Nevertheless, ischemia may result in altered ionic transport, altered autonomic tone, and injury to the conduction system, resulting in a variety of ischemia-induced arrhythmias and conduction abnormalities.

Pathophysiology and Consequences of Myocardial Ischemia

Angina Pectoris

In the normal myocardium, a balance between myocardial oxygen supply and demand is present at rest and during physical exertion or emotional excitement. In response to an increase in oxygen demand, an appropriate increase in oxygen supply maintains adequate tissue oxygenation. When oxygen demand increases in the setting of limited oxygen supply, myocardial ischemia results. At rest, the myocardium extracts most of the oxygen that is delivered to it through the coronary arteries. As a result, any increase in myocardial oxygen demand, as a result of an increase in heart rate, wall stress, or contractility, must be accompanied by a concomitant proportional increase in myocardial blood flow. Regulation of coronary blood flow occurs at the level of the arterioles and is dependent on autonomic tone and an intact, functioning endothelium.

For many years, patients with chronic, stable angina pectoris were believed to develop myocardial ischemia because of a transient increase in myocardial oxygen demand as a result of physical exertion or emotional excitement in the setting of limited oxygen supply caused by fixed atherosclerotic CAD. Effort-induced angina was thought to be a problem of excessive oxygen demand with limited oxygen supply. However, some patients with chronic, stable angina may develop myocardial ischemia because of dynamic coronary vasoconstriction in the setting of fixed atherosclerotic CAD. Such inappropriate coronary vasoconstriction has been shown to occur during exposure to cold, while under mental stress, and during isometric or isotonic exercise as well as during exposure to cigarette smoking. In short, chronic, stable angina is a syndrome of both increased myocardial oxygen demands in the setting of limited supply and dynamic reductions in myocardial oxygen supply, most of which are induced by common, everyday events.

Chapter 9—Coronary Heart Disease

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Table 9-2 Angina Pectoris Type

Pattern

ECG

Abnormality

Medical Therapy

Stable

Stable pattern, induced by physical exertion, exposure to cold, eating, emotional stress Lasts 5-10 min Relieved by rest or nitroglycerin

Baseline often normal or nonspecific ST-T changes

≥70% Luminal narrowing of one or more coronary arteries from atherosclerosis

Aspirin Sublingual nitroglycerin

Unstable

Prinzmetal or variant angina

Increase in anginal frequency, severity, or duration Angina of new onset or now occurring at low level of activity or at rest May be less responsive to sublingual nitroglycerin Angina without provocation, typically occurring at rest

Signs of previous MI ST-segment depression during angina Same as stable angina, although changes during discomfort may be more pronounced Occasional ST-segment elevation during discomfort

Plaque rupture with platelet and fibrin thrombus, causing worsening coronary obstruction

Anti-ischemic medications Statin Aspirin and clopidogrel Anti-ischemic medications Heparin or LMWH Glycoprotein IIb/IIIa inhibitors Statin

Transient ST-segment elevation during pain Often with associated AV block or ventricular arrhythmias

Coronary artery spasm

Calcium channel blockers Nitrates

AV, atrioventricular; ECG, electrocardiography; LMWH, low-molecular-weight heparin; MI, myocardial infarction.

The patient with exertional angina pectoris (Table 9-2) usually complains of a retrosternal pressure or dull ache during physical exertion, while eating, during exposure to cold, or with emotional excitement. Other adjectives that the patient may use to describe the chest discomfort include “viselike,” “constricting,” “crushing,” “heavy,” and “squeezing.” In many patients, the retrosternal pain radiates to the jaw, neck, and left shoulder and arm. Dyspnea often accompanies exertional angina pectoris and may be associated with diaphoresis and nausea. Although its duration varies considerably from one patient to another, the episode usually lasts 3 to 10 minutes. On occasion, however, it may linger for as long as 20 to 30 minutes. It is typically relieved by sublingual nitroglycerin within 1 to 3 minutes. At a time when the patient is not experiencing angina, the physical examination is usually normal. During an episode of chest discomfort, the patient may become somewhat pale and diaphoretic, and the respiratory rate and effort may increase. The heart rate and systemic arterial pressure are usually greater than at rest. Pulmonary congestion (e.g., rales at both bases posteriorly) may be evident. On auscultation of the heart, an S4 is usually audible as a result of decreased left ventricular compliance, and a transient S3 may be present if left ventricular systolic dysfunction occurs. In an occasional patient, ischemia-induced papillary muscle dysfunction will cause a murmur of mitral regurgitation to be audible at the cardiac apex. As the episode of angina resolves, the pulmonary rales, diastolic heart sounds, and systolic murmur may quickly disappear. Three noninvasive techniques have been used to demonstrate transient episodes of myocardial ischemia in the patient with exertional angina pectoris: (1) During exerciseinduced or spontaneous chest pain, the ECG usually shows ST-segment depression that is reflective of subendocardial

ischemia, which resolves within minutes of the pain’s disappearance (Fig. 9-2). (2) During episodes of angina, global left ventricular systolic function may decline, and segmental wall motion abnormalities may develop. These abnormalities can be observed with two-dimensional echocardiography, magnetic resonance imaging, or gated blood pool scintigraphy. The assessment of regional abnormalities and systolic function using two-dimensional echocardiography performed during exercise or intravenous dobutamine infusion is a particularly useful technique for detecting myocardial ischemia. As with the ECG alterations, these segmental wall motion abnormalities may resolve within minutes after relief of pain, or they may linger for hours. (3) Myocardial perfusion may be assessed during exercise-induced angina by the intravenous injection of a radioactive tracer, such as thallium-201 or technetium sestamibi, followed by imaging with the appropriate equipment.

EVALUATION OF THE PATIENT WITH ANGINA For the patient in whom the cause of chest pain is unclear, stress testing may help clarify the diagnosis by reproducing the patient’s symptoms and demonstrating objective evidence of ischemia. Submitting the patient to exercise or pharmacologic stress provides an opportunity to assess the evidence of ischemia through the evaluation of ECG abnormalities (e.g., routine stress testing), perfusion defects (e.g., radionuclide imaging), or segmental wall motion abnormalities (e.g., echocardiography). As with all diagnostic tests, the predictive value of exercise testing is influenced by the pre-test probability that the patient has CAD. For example, in the patient with a high pre-test probability of having CAD, a positive test is highly predictive, whereas a test with

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Boston University Hospital

1 MAR 1999

I

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

I

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

A

B Figure 9-2 Electrocardiogram obtained during angina (A) and after the administration of sublingual nitroglycerin and subsequent resolution of angina (B). During angina, transient ST-segment depression and T-wave abnormalities are present.

negative results has a high likelihood of being falsely negative. Conversely, in the individual with a low likelihood of having CAD, a negative test is highly predictive, but a positive test result has a high likelihood of being falsely positive. Stress testing may also be useful in the patient with chronic stable angina for the determination of exercise capacity, documentation of the effectiveness of medications, and risk stratification (i.e., identifying patients at risk for CAD in whom more aggressive therapies may be warranted) (Fig. 9-3). The Clinical Outcomes Utilizing Revascularization and

Aggressive Drug Evaluation (COURAGE) trial has demonstrated that patients with a large degree of ischemic myocardium during stress testing are most likely to benefit with coronary revascularization. In a patient with a normal resting ECG, routine stress testing with ECG monitoring is usually sufficient. However, in patients with baseline ECG abnormalities (e.g., nonspecific ST-segment abnormalities, left ventricular hypertrophy, left bundle branch block [LBBB], or ventricular pre-excitation) and in patients taking digoxin, the specificity of exercise-induced ST-T-wave changes is diminished. In these

Chapter 9—Coronary Heart Disease 1 min 30 sec of recovery

Standing at rest 138/90

II

V2

II

V2

101

166/94 HR: 98

HR: 58 Moderate chest pain 162/94

Submaximal exercise

6 min of recovery

HR: 115

HR: 82

Mild chest pain 164/94

108/90

Chest pain resolved

Maximal exercise

HR: 127

10 min of recovery 104/90 HR: 87

Moderate chest pain Figure 9-3 Treadmill exercise test demonstrates a markedly ischemic electrocardiogram (ECG) response. The resting ECG is normal. The test was stopped when the patient developed angina at a relatively low workload, accompanied by ST-segment depression in lead II and ST-segment elevation in lead V2. These changes worsened early in recovery and resolved after administration of sublingual nitroglycerin. Only leads II and V2 are shown; however, ischemic changes were seen in 10 of the 12 recorded leads. Severe atherosclerotic disease of all three coronary arteries was documented at subsequent cardiac catheterization.

individuals, echocardiographic, nuclear scintigraphic, or magnetic resonance imaging improves both the sensitivity and the specificity of stress testing, albeit at substantially increased cost. Nuclear imaging is preferred over echocardiography in patients with LBBB. Exercise-induced ECG changes in women are less specific than in men; for this reason, many physicians perform exercise testing with imaging in all women. Several prognostic markers associated with a poor clinical outcome have been identified in the patient undergoing routine stress testing; these include (1) ischemic ECG changes (ST-segment depression) that occur early in exercise, in multiple leads, or persist for several minutes after the completion of exercise; (2) an associated decrease (rather than the normal increase) in blood pressure levels; and (3) poor exercise tolerance (e.g., less than 6 minutes exercise duration on the standard Bruce protocol). In patients whose baseline ECG is sufficiently abnormal to preclude an adequate interpretation during exercise, the standard exercise test may be combined with radionuclide perfusion imaging, ECG assessment of left ventricular global and segmental function, or magnetic resonance imaging of left ventricular function. When stress testing is combined with imaging, the sensitivity for detecting CAD is about 90%, which is greater than that achieved with standard ECGguided exercise testing. The specificity is about 80%, and the predictive value is about 90%. When a radionuclide stress perfusion imaging study is performed, a radioactive tracer, such as thallium-201, technetium-99m sestamibi, or technetium-99 tetrofosmin, is immediately administered intravenously before exercise is terminated. Because the radioactive tracer is distributed to the myocardium in proportion to coronary arterial blood flow, segments of myocardium that become ischemic during exercise have decreased uptake of the radioactive tracer relative to normally perfused areas of myocardium. Within 4

hours of the injection of thallium, about 50% is redistributed throughout viable myocardium, which results in a filling in of areas that were hypoperfused at peak exercise. Unlike thallium, technetium sestamibi and tetrofosmin do not redistribute to areas that were ischemic. The presence and extent of exercise-induced perfusion abnormalities provide prognostic information. Patients with a normal stress perfusion study—with or without CAD—have an extremely low risk for future cardiac events (75th percentile of patient’s age and sex for coronary calcification), hsCRP > 3 mg/dL, or metabolic syndrome. CAD, coronary artery disease; CRP, C-reactive protein; HDL, highdensity lipoprotein; hsCRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; TG, triglycerides.

been established (Table 9-4). Patients should be instructed on dietary changes; an evaluation by a nutritionist may be helpful. Patients with CAD generally should be treated aggressively for hyperlipidemia management. Statin medications are most commonly prescribed for a goal LDL lower than 100 mg/dL. Recent studies suggest that further LDL reductions below 70 mg/dL provide further risk reduction. For those CAD patients with normal cholesterol levels, statin therapy may be helpful in stabilizing atherosclerotic plaque, resulting in a reduced risk for MI and stroke. For those with low HDL, niacin or fibrate agents may be helpful, in addition to aerobic exercise, to achieve a goal HDL of greater than 40 mg/dL. All patients with known or suggested CAD should be placed on antiplatelet therapy (e.g., aspirin, 75 to 325 mg daily; clopidogrel, 75 mg daily for patients allergic to aspirin) unless a contraindication to antiplatelet therapy is present. These agents decrease the rates of MI and death in patients with angina or previous MI. In addition, they may decrease the risk for MI in individuals without suggested CAD but with multiple risk factors. Angiotensin-converting enzyme (ACE) inhibitors should be prescribed to patients with CAD who have diabetes mellitus or left ventricular systolic dysfunction unless contraindicated. Angiotensin receptor

Chapter 9—Coronary Heart Disease blockers may be used in patients who develop an ACE inhibitor–induced dry cough. Although exercise is often limited by angina, regular activity at a level that is tolerated should be encouraged. Isometric exercise, such as weight lifting and high-intensity activities, especially in the cold (e.g., skiing, shoveling snow), are not advisable. However, many patients with stable angina may perform vigorous activities, including moderate physical exertion at work. For obese patients and those with a sedentary lifestyle, regular aerobic activity is recommended. As previously noted, the pathophysiologic characteristics of angina are one of supply-demand mismatch. Therefore, its therapy is directed at correcting the mismatch by decreasing myocardial oxygen demands, augmenting myocardial oxygen supply, or both. Nitrates, β blockers, and calcium channel blockers are among the pharmacologic options most commonly used for the control of symptoms in patients with chronic stable angina (Table 9-5). They appear to be of similar efficacy in controlling anginal symptoms. When a single agent fails to control angina, combination therapy is usually effective. Ranolazine, a selective inhibitor of late sodium influx, is an effective antianginal agent that has no effect on heart rate or systemic blood pressure. Ranolazine may be used as either a first- or second-line agent for patients with angina. Unlike aspirin and lipid-lowering therapy, none of these agents has been convincingly shown to decrease mortality in patients with CAD.

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Nitrate preparations have been used in the medical management of exertional angina for many years. The effect of nitrates is mediated through relaxation of vascular smooth muscle. Dilation of arterioles reduces systemic vascular resistance and therefore afterload. Nitrates have a more pronounced effect on the venous system; venodilation results in venous pooling, decreased venous return, and therefore decreased preload. The arteriolar and venodilatory effects substantially reduce myocardial oxygen demands, thereby decreasing angina. In addition, nitrates augment coronary blood flow by dilating epicardial coronary arteries (although this effect is minimal in extensively diseased arteries) and increasing blood flow through collateral vessels. Several formulations are available. Sublingual nitroglycerin tablets or oral spray is effective for the acute treatment of anginal episodes and as prophylactic therapy before an activity that is likely to provoke angina. Topical nitroglycerin ointment and oral preparations are effective for the chronic management of stable angina, whereas intravenous nitroglycerin is appropriate for patients with unstable angina and acute MI. The chronic use of nitrates may result in tolerance, an effect that can be minimized by allowing for a daily nitrate-free period; for example, removing topical nitrate preparations during sleeping hours or prescribing oral nitrates that avoid aroundthe-clock administration. β-adrenergic blocking drugs are competitive inhibitors of catecholamine β receptors. They decrease myocardial oxygen

Table 9-5 Medications for Angina Pectoris Drug Class

Examples

Nitroglycerin

Sublingual Topical Intravenous Oral

β-adrenergic blocking agents

Metoprolol Atenolol Propranolol

Calcium channel blocking agents

Nadolol Phenylalkylamine (verapamil) Benzothiazepine (diltiazem)

Calcium channel blocking agents

Dihydropyridine (nifedipine, amlodipine)

Late sodium current blocking agents

Ranolazine

AV, atrioventricular; INa, sodium current.

Anti-anginal Effect

Physiologic Side Effects

Decreased preload and afterload Coronary vasodilation Increased collateral blood flow Decreased heart rate Decreased blood pressure Decreased contractility

Headache Flushing Orthostasis

Tolerance develops with continuous use

Bradycardia Hypotension

May worsen heart failure and AV conduction block; avoid in vasospastic angina

Decreased heart rate Decreased blood pressure Decreased contractility Coronary vasodilation Decreased blood pressure Coronary vasodilation Inhibits cardiac late INa Prevents calcium overload

Bronchospasm Depression Bradycardia Hypotension

Comments

May worsen heart failure and AV conduction

Constipation with verapamil

Hypotension, reflex tachycardia Peripheral edema Dizziness Headache Constipation Nausea

Short-acting nifedipine associated with increased risk for cardiovascular events No effects on blood pressure or heart rate Modest QTc prolongation

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demands by reducing heart rate, blood pressure, and contractility. These agents are effective in controlling anginal symptoms (especially exercise-induced symptoms), and they decrease mortality and reinfarction in survivors of MI. β blockers differ in their lipid solubility, duration of action, and β-receptor selectivity. β1 receptors predominate in the heart, where they mediate increases in heart rate, contractility, and atrioventricular (AV) conduction. β2 receptors predominate in the vascular and bronchial smooth muscle. Blockade of β1 receptors produces several beneficial cardiac effects, whereas β2-receptor blockade may induce broncho spasm and peripheral vasoconstriction. Atenolol and metoprolol are β1 selective at low doses; however, at the moderate to high doses often used in clinical practice, all β blockers lose their selectivity. Because β blockers may worsen underlying conduction system abnormalities, they should be used with caution in patients with conduction system dysfunction. In addition, these agents may result in a mild increase in the triglyceride level and a mild decrease in the HDL cholesterol level. Calcium ions play a critical role in myocardial and vascular smooth muscle contraction and in the genesis of the cardiac action potential (see Chapter 10). Blocking these effects with a calcium antagonist results in a decrease in heart rate, myocardial contractility, and peripheral arterial vasodilation, all of which decrease myocardial oxygen demand. In addition, coronary vasodilation occurs, resulting in augmented oxygen supply. Three major classes of calcium antagonists are available, and the specific agent of choice should be individualized for the particular patient. The dihydropyridine medications (e.g., nifedipine, amlodipine) predominantly cause vasodilation with little or no effect on heart rate, contractility, or AV conduction. In fact, the vasodilation may lead to a reflex tachycardia. The phenyl alkylamine medications (e.g., verapamil) reduce heart rate, slow AV conduction, depress contractility, and have less of an effect on peripheral vascular tone than the dihydropyridine medications. They may not be tolerated in patients with depressed ventricular systolic function or underlying conduction system disease. The benzothiazepine medications (e.g., diltiazem) have less vasodilatory action than the dihydropyridine medications and less myocardial suppressant action than the phenylalkylamine medications.

REVASCULARIZATION IN PATIENTS WITH ANGINA In patients for whom medical therapy does not effectively control anginal symptoms and in patients considered to be at increased risk clinically (e.g., unstable angina, angina associated with heart failure, angina associated with arrhythmia, poor exercise capacity) or by noninvasive testing (e.g., large amount of ischemic myocardium, depressed left ventricular systolic function), coronary revascularization plays an important therapeutic role. Several modalities for coronary revascularization exist, including surgical revascularization (e.g., coronary artery bypass grafting [CABG]) and catheter-based percutaneous techniques (e.g., percutaneous coronary intervention [PCI]). With advances in equipment, adjunctive pharmacologic agents, and increasing operator experience, PCI can now be achieved with high success rates and at relatively low risk.

More than 1 million PCI procedures are performed each year in the United States alone. (Web video 9-1—Angioplasty, http://www.heartsite.com/html/ptca.html). With percutaneous transluminal coronary angioplasty (PTCA), a highpressure inflation of a distensible balloon is performed at the site of coronary arterial narrowing with resultant enlargement of the lumen. Balloon inflation causes denudation of the endothelial surface, fracture of the atherosclerotic plaque, and disruption of the vessel intima. The vessel lumen can be successfully dilated in greater than 90% of cases. In 2% to 5% of patients undergoing PTCA, the coronary arterial injury is severe, and, as a result, the artery occludes abruptly. Such patients are usually treated with intracoronary stenting or rarely urgent CABG to prevent acute MI. In patients in whom PTCA is initially successful, up to 50% develop restenosis at the site of balloon dilation within 1 to 6 months of the angioplasty. Of the patients who develop restenosis, about 50% experience recurrent angina. Restenosis is a complex process involving elastic recoil of the artery, vascular remodeling, and hyperplasia of the vascular intima. It is not prevented by the administration of antiplatelet, anticoagulant, anti-anginal, or hypolipidemic medications. During the past decade, intracoronary stenting now has become the technique of choice for PCI (Web video 9-2—Intracoronary Stenting, http://www.heartsite.com/ html/stent.html). The coronary stent—a cylindric, expandable metal structure available in varying diameters and lengths—is premounted on an angioplasty balloon. When the balloon is positioned at the site of the stenosis and inflated to expand the stent, the stent becomes permanently embedded in the arterial wall. Subsequently, the balloon is deflated and removed, but the stent maintains its expanded cylindric configuration, thereby acting as a scaffold to maintain vessel patency. In this way, stenting results in a greater increase in luminal size than can be achieved with balloon angioplasty alone (see Fig. 9-1B). Stents can be used to treat PTCA-related coronary arterial dissections, thereby avoiding the need for urgent CABG. In comparison with balloon angioplasty, stenting is associated with a reduced incidence of abrupt closure (about 1% to 2%) and restenosis (about 20% to 25%), thereby explaining why it is the procedure of choice in more than 90% of PCIs. At the same time, stenting may not be the procedure of choice in small coronary arteries (luminal diameter < 2.0 mm) because these vessels are too small for the smallest available stents. The person in whom intracoronary bare metal stenting (BMS) has been performed should receive aspirin indefinitely and clopi dogrel for 2 to 4 weeks to prevent thrombosis. During the weeks after stent deployment, the stent becomes endothelialized, at which time it is no longer thrombogenic or subject to abrupt closure. Studies have demonstrated that a 1-year course of clopidogrel is superior compared with a 4-week course after bare metal stenting, with a reduction in adverse ischemic events. Beginning in 2003, drug-eluting stents (DES) have been coated with antiproliferative drugs (e.g., sirolimus [Rapamycin], paclitaxel [Taxol]), which are extremely effective in preventing restenosis. There are five FDA-approved DES in the United States, listed in order of their approval with the year of approval: Cordis Cypher (sirolimus; 2003), Boston Scientific Taxus (paclitaxel; 2004), Medtronic Endeavor (zotarolimus; 2007), Abbott Xience V (everolimus;

Chapter 9—Coronary Heart Disease 2008), and Boston Scientific Promus (everolimus; 2008). The incidence of restenosis with DES is 5% to 10%. Ran domized trials have demonstrated a roughly 70% reduction in stent restenosis with DES compared with BMS. In stenting procedures in the United States, roughly 65% involve DES, and 35% involve BMS. The person who receives a DES should take aspirin indefinitely and clopidogrel for at least 12 months. The antiproliferative agent that coats the stent delays the process of endothelialization; as a result, these stents are subject to thrombosis and abrupt closure for months after their placement. Other percutaneous interventional techniques that have a limited role in coronary revascularization include rotational and directional atherectomy; thrombectomy; brachytherapy, which is the application of local radiation therapy to treat restenosis after stenting; and coronary laser therapy. Of these, thrombectomy has the most promising role in PCI procedures for STEMI patients. Studies performed in the 1970s and 1980s established the effectiveness of CABG for the control of anginal symptoms and, in some patients, offered an improvement in survival when compared with anti-anginal medical therapy. Harvesting a segment of saphenous vein or radial artery and anastomosing it to the ascending aorta (proximally) and the distal portion of the diseased coronary artery (distally) is performed with CABG. The internal mammary artery can be dissected free from the pleural surface and its distal end anastomosed to a diseased coronary artery. These procedures effectively bypass the sites of atherosclerotic narrowing, thereby allowing blood to flow freely to the myocardium perfused by the diseased artery. The left internal mammary artery is most commonly used to bypass the left anterior descending coronary artery, and has 10-year patency rates of roughly 90%. In comparison, the patency rate for saphenous vein grafts is 50% at 10 years. Whenever possible, the mammary artery is used because its long-term patency is superior to that of venous or radial arterial conduits. Experienced surgeons perform CABG with a peri-operative mortality rate of 1% to 2%, a stroke rate of 1% to 2%, and a peri-operative MI rate of 5% to 10%. CABG improves survival (when compared with medical therapy) in patients with greater than 50% luminal diameter narrowing of the left main coronary artery or narrowing of all three major epicardial coronary arteries in conjunction with mildly or moderately depressed left ventricular systolic function (e.g., ejection fraction, 35% to 50%). In addition, CABG improves long-term survival in patients with a narrowing of two or three epicardial coronary arteries and normal left ventricular systolic performance, provided that the proximal portion of the left anterior descending coronary artery is significantly narrowed. In the short term (within 1 to 2 years of the procedure), those having PCI are more likely than those undergoing CABG to require anti-anginal medications or a subsequent revascularization procedure largely because of the incidence of symptomatic restenosis after successful percutaneous coronary revascularization. Because of the progressive decline of graft patency between 5 and 10 years postoperatively, the benefits of surgery over percutaneous revascularization are less apparent in the long term. Small, randomized studies comparing the two approaches to revascularization in patients with multivessel CAD and preserved left ven-

105

tricular systolic function (e.g., ejection fraction > 50%) demonstrate no difference in mortality after 1 to 5 years of follow-up, except in patients with diabetes, who fare better with CABG. Recently, however, larger observational studies showed that CABG is associated with higher long-term survival than stenting in patients with multivessel CAD. A recently completed trial showed no difference between CABG and DES for left main or multivessel CAD in mor tality or myocardial infarction. DES did have higher rates of repeat revascularization because of restenosis, but lower rates of stroke. There are ongoing randomized trials in diabetic patients with multivessel CAD randomized to CABG or DES. Unfortunately, neither percutaneous nor surgical revascularization techniques halt the underlying atherosclerotic process, and new stenoses may develop at previously uninvolved sites in native coronary arteries and in the bypass grafts. Aspirin should be administered immediately after CABG and continued thereafter because it improves graft patency. If a stenosis develops in a bypass graft, percutaneous revascularization is often effective. In addition, repeat CABG is possible, although the surgical risks are higher than with the first procedure. For patients with severe angina refractory to maximal medical therapy and coronary revascularization, treatment options include external counterpulsation and spinal cord stimulation. External counterpulsation involves inflation of three lower extremity cuffs during diastole and deflation during systole. This treatment is performed in 1-hour sessions for a total of 35 treatments. Roughly 75% of patients report an improvement in angina severity, and the treatment is generally well-tolerated. The likely mechanism of action involves improved endothelial function. Spinal cord stimulation provides analgesia for patients with severe angina by placing a stimulating electrode in the dorsal epidural space at the C7-T1 level. Although preliminary data appear promising, there is a paucity of data on intermediate- or longterm outcomes. Transmyocardial laser revascularization is no longer recommended for refractory angina.

VARIANT ANGINA In 1959, Prinzmetal and colleagues described a group of patients with variant angina. These patients usually experienced chest pain at rest rather than with physical exertion or emotional excitement, and the ECG recorded during chest pain showed ST-segment elevation rather than depression, which resolved as the pain subsided (Fig. 9-4). On occasion, episodes of chest discomfort were accompanied by varying degrees of AV block or ventricular ectopy, but MI was uncommon. Patients with variant angina did not often have the usual risk factors for coronary atherosclerosis, although cigarette smoking was frequent. Subsequent angiographic studies demonstrated that variant angina is the result of epicardial coronary arterial spasm, which may occur either at the site of an atherosclerotic plaque or in the setting of angiographically normal coronary arteries. During coronary angiography, coronary vasospasm may be provoked by the intracoronary infusion of acetylcholine or ergonovine. In addition, methacholine, a parasympathomimetic agent, has been used to induce coronary arterial spasm, similar to the arterial spasm in response to exposure

106


Figure 9-4 Continuous electrocardiogram recording in a patient with Prinzmetal (variant) angina. The spontaneous onset of chest discomfort began during the top strip, accompanied by transient ST-segment elevation. By the bottom strip, several minutes later, both discomfort and ST-segment elevation had resolved.

to cold (e.g., cold pressor test), the production of a significant alkalosis (e.g., vigorous hyperventilation during the intravenous infusion of an alkalotic buffer solution), and histamine administration. Calcium channel blockers, alone or in combination with long-acting nitrate preparations, are highly effective in patients with coronary arterial spasm. They are the treatment of choice for patients with variant angina. β blockers are contraindicated in patients with vasospastic angina because blockade of the vasodilatory effects of β2-receptor stimulation may result in unopposed α-adrenergic vasoconstriction. For the rare patient who has continued episodes of coronary arterial spasm despite maximal medical therapy, intracoronary stenting may be performed.

Acute Coronary Syndromes The term acute coronary syndrome encompasses the clinical syndromes of unstable angina, NSTEMI, and STEMI. Patients with unstable angina or NSTEMI are usually indistinguishable by history, physical examination, and ECG findings. The distinction between these two groups is made only after the results of the serum cardiac enzyme analyses are available. The patient with unstable angina or NSTEMI may develop myocardial ischemia or MI through several mechanisms. Most commonly, these individuals have subendocardial ischemia or necrosis as a result of decreased coronary blood flow, which is due to platelet aggregation or a partially occlusive intracoronary thrombus at the site of an ulcerated atherosclerotic plaque. In addition, concomitant plateletmediated coronary arterial vasoconstriction at the site of plaque ulceration may occur. Alternatively, the patient may develop myocardial ischemia or MI because of an increase in myocardial oxygen demand that cannot be met by an appropriate increase in coronary blood flow. In some indi-

viduals, the coronary blood flow cannot appropriately increase because of severe CAD. In those without CAD, subendocardial ischemia or infarction may occur solely as a result of significantly augmented myocardial oxygen demands in the setting of a normal supply (e.g., uncontrolled hypertension, thyrotoxicosis) or a decrease in myocardial oxygen delivery (e.g., profound anemia, hypoxemia). Patients with left ventricular hypertrophy (due to hypertension or aortic stenosis) are at increased risk for subendocardial ischemia. The patient with unstable angina pectoris usually complains of retrosternal chest pain similar in character and consistency to that of the patient with stable, exertional chest pain. In contrast to the patient whose angina is stable, however, these individuals usually report that their anginal frequency, severity, or duration has worsened, and they may report pain at rest. Furthermore, the patient may note that nitroglycerin is ineffective or less effective in relieving the chest pain. On physical examination, the patient may exhibit no visible or audible abnormalities at a time when he or she is pain free. During an episode of chest pain, however, the patient may become anxious, diaphoretic, and dyspneic. The heart rate often increases, although bradycardia may occur secondary to enhanced vagal tone or transient AV block and most commonly with inferior wall ischemia or infarction. On cardiac auscultation, an S4 may be audible as a result of decreased left ventricular compliance. An S3 may be present if left ventricular systolic dysfunction occurs, and a systolic murmur of mitral valve papillary muscle dysfunction may be appreciated. Evidence of pulmonary congestion is often present and may reflect an elevated left ventricular filling pressure as a result of decreased left ventricular compliance or systolic dysfunction. If a large area of myocardium is involved and left ventricular systolic dysfunction ensues, then frank pulmonary edema may occur. For the patient who is experiencing chest pain, a 12-lead ECG should be immediately obtained because it is frequently diagnostic of myocardial ischemia or MI and is important

Chapter 9—Coronary Heart Disease 10 mm/mV 25 mm/s Filter ON 1-11-111

aVR aVL aVF

10 mm/mV V1-V2-V3

107

V4-V5-V6

Figure 9-5 Acute anterolateral myocardial infarction. Leads I, aVL, and V2 to V6 demonstrate ST-segment elevation. Reciprocal ST-segment depression is seen in leads II, III, and aVF. Deep Q waves have developed in leads V2 and V3.

in determining the appropriate treatment plan. STEMI, previously referred to by the pathologically inaccurate term, transmural infarction or Q-wave myocardial infarction, refers to an acute coronary syndrome in which ST-segment elevation (e.g., ST-segment elevation at the J point in two contiguous leads at least 0.2 mV in men or at least 0.15 mV in women in leads V2 to V3 or at least 0.1 mV in other leads) is present on the surface ECG. These infarctions typically are the result of complete thrombotic occlusion of a coronary artery and may first be exhibited on the ECG by symmetrically peaked or hyperacute T waves. These peaked T waves resolve after several minutes as the characteristic ST-segment elevation develops (Fig. 9-5). The distribution of leads with ST-segment elevation can identify the myo cardial location and the culprit coronary artery: anterior MI, V2 to V5, left anterior descending coronary artery; inferior MI, II, III, aVF, right coronary artery; lateral MI, I, aVL, V6, left circumflex or diagonal; posterior, V7 to V9, left circumflex coronary artery; right ventricular RV4, right coronary artery. NSTEMI, previously termed subendocardial infarction or non–Q-wave myocardial infarction, and unstable angina occur as a result of a subtotally occlusive thrombus or a thrombus that was initially totally occlusive but not sustained, enabling partial or complete lysis to occur within minutes to hours of its formation. They are associated with ST-segment depression and T-wave inversions on the surface ECG (Fig. 9-6). In one fourth to one half of patients with acute MI, the first ECG does not demonstrate typical ST-segment changes. In this situation, serial ECGs should be obtained to increase the diagnostic yield. If a patient has ongoing chest pain without ST-segment changes, posterior lead ECG recording of leads V7 to V9 should be performed. A posterior lead ECG is used to assess for posterior wall injury, usually the result of left circumflex coronary artery occlusion, which is not readily apparent on a standard 12-lead ECG. If acute MI is

suggestive but the initial ECG does not confirm the diagnosis, demonstration of new regional wall motion abnormalities with echocardiography may be helpful in confirming the diagnosis. Myocardial necrosis results in the release of certain intracellular enzymes into the blood. Their appearance in the blood allows the identification of myocardial necrosis, and their quantitation over a number of hours allows for the estimate of its amount. Because 20% of patients with acute MI have atypical or no symptoms (i.e., silent MI) and the initial ECG is nondiagnostic in up to 50% of patients, serologic identification of myocyte necrosis has become an important diagnostic tool. Several serum markers have been identified (Fig. 9-7). Creatine kinase (CK) and its myocardial-specific isoenzyme, creatine kinase muscle band (CK-MB) are detectable in the blood within 3 to 6 hours of the onset of MI. They reach their peak concentration at 24 hours and return to normal within 48 hours. Although CK-MB is relatively specific for cardiac injury, it may be elevated in subjects with extensive skeletal muscle injury or disease, chronic renal disease, or hypothyroidism. Troponins I and T are regulatory proteins involved in the interaction of cardiac actin and myosin. Because they are not present to any extent in other organs and are not detectable in blood under normal circumstances, an increase in their serum concentration is more specific and sensitive for myocyte necrosis than an increase in the concentration of other enzymes. After cardiac injury, the serum troponin concentration begins to rise within 4 to 6 hours and remains elevated for 7 to 10 days. False-positive elevations of troponin T, but not troponin I, have been observed in patients with renal failure. The presence of heterophilic antibodies or fibrin may interfere with the assay for troponin I and give false-positive results. The former is found in 3% of the general population and a high percentage of patients with autoimmune disease; the latter may be found in blood that

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Boston University Hospital I

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

Figure 9-6 Marked ST-segment depression in a patient with prolonged chest pain is the result of an acute non–ST-segment elevation myocardial infarction (NSTEMI). Between 1 and 3 mm of ST-segment depression is seen in leads I, aVL, and V4 to V6. The patient is known to have had a previous inferior myocardial infarction.

heart rate or blood pressure, pulmonary embolism, hypoxemia) or reduced supply (i.e., hypotension) in the absence of epicardial CAD.

CPK

Serum enzyme level

TREATMENT OF UNSTABLE ANGINA AND NON–ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION cTnl, cTnT

LDH AST Normal

5

10 15 Days after infarction Figure 9-7 Typical time course for the detection of enzymes released after myocardial infarction. AST, serum aspartate aminotransferase; CPK, creatine kinase; cTnI, cardiac troponin I; cTnT, cardiac troponin T; LDH, lactate dehydrogenase.

has been heparinized. Because serum troponin concentration is an extremely sensitive measure of myocardial necrosis, such elevations are sometimes observed in patients with myocardial necrosis as a result of increased myocardial oxygen demand (i.e., subjects with a significantly elevated

Unstable angina and NSTEMI may be clinically indistinguishable with ECG studies. They are differentiated only by the presence of serologic evidence of myocardial necrosis. Accordingly, the initial treatment of these patients is similar and includes (1) hospital admission with serial assessment of ECGs and sequential measurements of cardiac enzymes; (2) aggressive anti-anginal, antiplatelet, and antithrombotic therapy; and (3) identification of the patient at increased risk for recurrent ischemia, MI, or death who may benefit from revascularization. With optimal medical therapy, the 1-year mortality rate of patients with unstable angina or NSTEMI is 3% to 5% (Fig. 9-8). Rest for 24 to 48 hours with continuous ECG monitoring, analgesics, and supplemental oxygen therapy are frequently prescribed. Sublingual nitroglycerin should be given initially, followed by oral or topical nitroglycerin. Intravenous nitroglycerin should be administered if recurrent chest pain occurs. In the absence of a contraindication, β blockers should be promptly instituted because they decrease heart rate and blood pressure levels and left ventricular contractility, thereby reducing myocardial oxygen demand. The calcium antagonists, verapamil and diltiazem, may be useful for the patient who fails to respond to nitrates and β blockers as well as for the patient with a contraindication to β blockers. However, calcium antagonists should not be used in the patient with known depressed left ventricular systolic function or with evidence of pulmonary vascular congestion on

Chapter 9—Coronary Heart Disease

109

Symptoms suggestive of an acute coronary syndrome

1. 12-Lead electrocardiogram 2. Aspirin 3. Supplemental oxygen 4. Sublingual nitroglycerin 5. Morphine PRN 6. Cardiac enzymes

No ST-segment changes Initial enzymes normal

Observe 1. Nitroglycerin PRN 2. Analgesia 3. Serial ECG and cardiac enzymes

ST-segment elevation consistent with STEMI

1. Clopidogrel 2. LMWH

1. IV nitroglycerin 2. Heparin 3. IV β blocker

Recurrent chest pain or serial studies positive

No high-risk markers No recurrent chest pain

No recurrent chest pain, serial studies negative

Provocative stress testing Negative results

ST-segment depression consistent with unstable angina or NSTEMI

Provocative stress testing Negative results Positive results

Positive results

High-risk markers present - elevated troponin - persistent/recurrent chest pain - persistent ST depression - associated heart failure - hemodynamic instability - LVEF 4 hours’ duration). t-PA and its derivatives do not elicit an antibody response or hypotension. t-PA is given as an initial bolus or front loaded, followed by a 90-minute infusion (15 mg as a bolus, another 50 mg infused over 30 minutes, and the remaining 35 mg infused over the next 60 minutes). r-PA is administered as a double bolus (two 10-unit boluses delivered 30 minutes apart), and TNK-tPA is administered as a single bolus (0.5 mg/kg to a maximum of 50 mg). Although r-PA and TNK-tPA are somewhat more likely than t-PA to restore early patency of the infarct-related artery, the mortality rate with these three agents is similar. Overall, thrombolytic therapy decreases short-term mortality in subjects with STEMI by about 20%. Angiographic studies comparing thrombolytic regimens demonstrate that restoration of blood flow in the infarct-related artery is faster and more complete with t-PA than with streptokinase, and this translates into a modestly decreased mortality rate with t-PA, especially when it is given in a front-loaded fashion. Specifically, in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, t-PA was associated with a statistically significant 1% absolute reduction in mortality when compared with streptokinase. Most of this benefit occurred in patients younger than 70 years within 4 hours of the onset of an anterior STEMI. In older patients, in patients more than 4 hours after symptom onset, and in those with an MI in a territory other than the anterior wall, the mortality difference between these two agents was negligible. The contraindications to thrombolytic therapy are listed in Table 9-8; they identify those with an unacceptably high risk for bleeding complications. The most catastrophic potential complication of thrombolytic therapy is intra cranial hemorrhage. This risk is substantially increased in patients with a history of hemorrhagic stroke, uncontrolled hypertension, body weight less than 70 kg, and age more than 65 years. Aspirin is an obligatory adjunct to thrombolysis; its use is associated with an additive benefit on mortality and a decrease in recurrent ischemic events. Clopidogrel therapy

Chapter 9—Coronary Heart Disease Table 9-8 Contraindications to Thrombolytic Therapy in Acute Myocardial Infarction

Table 9-9 Complications of Acute Myocardial Infarction

Absolute

Left ventricular failure Right ventricular failure Cardiogenic shock

Suspected aortic dissection Active bleeding* Any prior cerebral hemorrhage Intracranial neoplasm Cerebral aneurysm or arteriovenous malformation Ischemic cerebrovascular accident within 3 months Relative Bleeding diathesis, coagulopathy, or anticoagulant use Major surgery within 3 weeks Puncture of a noncompressible vessel, internal bleeding, or head or major body trauma within previous 2 weeks Nonhemorrhagic stroke or gastrointestinal hemorrhage within 6 months Proliferative retinopathy Active peptic ulcer disease History of chronic, severe, poorly controlled hypertension Severe uncontrolled hypertension on presentation (systolic blood pressure > 180 mm Hg or diastolic blood pressure >110 mm Hg) Traumatic or prolonged (>10 min) cardiopulmonary resuscitation Pregnancy *Does not include menstrual bleeding.

with a 300-mg load followed by a daily maintenance dose of 75 mg improves mortality compared with placebo in STEMI patients 75 years and older. Intravenous heparin administered for 48 hours is necessary to maintain patency of the infarct-related artery after successful thrombolysis when a t-PA is administered, but not with streptokinase. Lowmolecular-weight heparin may be slightly more effective than unfractionated heparin as adjunctive therapy after successful thrombolysis. Its use is associated with a higher rate of vessel patency and a lower rate of reocclusion, leading to fewer episodes of recurrent ischemia and infarction, albeit with a somewhat increased risk for hemorrhagic complications. For patients who do not reperfuse within 90 minutes of receiving thrombolytics (as evidenced by continued chest pain or continued ST-segment elevation), rescue PCI is generally recommended. Even with successful thrombolysis, there is a 30% chance of culprit vessel reocclusion within 3 months. Risk stratification with a submaximal, symptomlimited stress test or coronary angiography is required during the STEMI hospitalization for thrombolized patients.

POST–MYOCARDIAL INFARCTION COMPLICATIONS The complications of MI may be categorized as electrical or mechanical (Table 9-9).

Arrhythmias and Conduction Abnormalities Cardiac arrhythmias may occur in patients with acute coronary syndromes. Those that cause symptoms or hemodynamic compromise almost always warrant treatment, whereas those that do not often can be managed expectantly.

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Functional

Mechanical Free-wall rupture Ventricular septal defect Papillary muscle rupture with acute mitral regurgitation Electrical Bradyarrhythmias (first-, second-, and third-degree atrioventricular blocks) Tachyarrhythmias (supraventricular, ventricular) Conduction abnormalities (bundle branch and fascicular blocks)

Although most of these arrhythmias are a direct result of the ischemic process, other reversible aggravating factors, such as electrolyte disturbances, hypoxemia, and medication toxicity, must be excluded. Premature ventricular complexes, ventricular couplets, and nonsustained ventricular tachycardia (VT) occur frequently in the peri-infarction period. Although such ectopy can be effectively suppressed with anti-arrhythmic agents, treatment is not warranted in the absence of symptoms or hemodynamic compromise. The presence of frequent ventricular ectopy does not predict the development of more malignant arrhythmias, and empiric therapy of such ectopy is associated with an increased mortality rate. Accelerated idioventricular rhythm, or slow VT, often occurs shortly after successful reperfusion, is self-limited, and does not require treatment. During the past several decades, mortality in hospitalized patients with acute MI has substantially declined in large part because of the early recognition and treatment of lethal arrhythmias. Because most deaths from acute MI occur as a result of sustained VT or ventricular fibrillation (VF), these rhythm disturbances should be treated with immediate electrical defibrillation, after which administering intravenous anti-arrhythmic medications (e.g., lidocaine, amio darone) is reasonable for 24 to 48 hours. Sustained but hemodynamically stable VT can be treated initially with anti-arrhythmic agents with electrical cardioversion held in reserve. In the absence of electrolyte abnormalities, polymorphic VT is usually a marker of recurrent or persistent ischemia, and aggressive anti-ischemic treatment is warranted. When sustained VT or VF occurs in the first 48 hours after MI, it does not portend the same poor prognosis as it does when it occurs later. Transient supraventricular tachyarrhythmias may occur in patients with acute MI, with sinus tachycardia and atrial fibrillation being the most common. The cause of sinus tachycardia (e.g., anxiety, pain, fever, anemia, hypoxemia, hypovolemia, pulmonary vascular congestion, thyrotoxicosis) should be promptly identified and corrected. If atrial fibrillation is accompanied by a rapid ventricular response, with resultant ongoing ischemia or hemodynamic compromise, electrical shock cardioversion should be considered. In the patient with atrial fibrillation and a rapid ventricular

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response, intravenous β blockers or amiodarone is usually effective for controlling the ventricular response, provided no contraindications to their use exist. Calcium channel blocking agents are also effective but should be avoided in the patient with heart failure. (These arrhythmias are discussed at length in Chapter 10.) Bradyarrhythmias may complicate acute MI. The most common bradyarrhythmia is sinus bradycardia, which is observed in 20% to 25% of patients with acute MI and is more common in those with inferior than anterior MI. In patients with inferior MI, sinus bradycardia is often associated with hypotension caused by increased vagal tone as a result of stimulation of vagal afferent fibers in the inferoposterior portion of the left ventricle (Bezold-Jarisch reflex). Unless accompanied by hemodynamic instability, sinus bradycardia should be simply observed. If treatment is necessary, intravenous atropine (0.5 to 2 mg) should be administered, aiming for a heart rate of 60 beats/minute and a resolution of symptoms. Temporary pacing is rarely required. Ischemia and infarction can result in transient or permanent injury to the conduction system. Varying degrees of AV block may occur in patients with acute MI. Ischemia of the AV node can result in first-degree or Mobitz type I second-degree (Wenckebach phenomenon) AV block. These rhythms are most often associated with inferior MI; they are transient, do not adversely affect survival, and do not require treatment unless the ventricular rate is sufficiently slow to produce syncope, congestive heart failure, or angina. Mobitz type II second-degree AV block is a rare complication of acute MI (1% of cases) and usually results from injury to the His-Purkinje system in the setting of an extensive anterior MI. It often is associated with progression to complete or third-degree AV block and is an indication for temporary transvenous or transcutaneous pacing in anticipation of implantation of a permanent pacemaker. Complete or thirddegree AV block may occur with inferior or anterior MI. When it occurs in the setting of an inferior MI, the block is usually at the level of the AV node. It is associated with a stable escape rhythm and tends to be transient, although it may take up to 1 to 2 weeks to resolve. As a result, treatment with only a temporary and not a permanent pacemaker is usually required. In contrast, when complete AV block occurs in the setting of an anterior MI, the His-Purkinje system is usually involved. The block is usually permanent, and a permanent pacemaker should be implanted. Block in one or more branches of the conduction system may occur with acute MI and is more common with anterior than with inferior infarction. Patients with isolated left anterior or left posterior fascicular block or right bundle branch block (RBBB) do not require specific therapy. Conversely, temporary pacing is suggested in patients with new bifascicular blocks (e.g., LBBB or RBBB with left anterior or left posterior fascicular block) because progression to complete heart block is common. If bifascicular block persists after an MI, a permanent pacemaker should be placed.

Congestive Heart Failure and Cardiogenic Shock Patients who die of cardiac failure after acute MI have extensive myocardial necrosis with loss of at least 40% of the functioning left ventricular muscle mass, as either a conse-

quence of new infarction or a combination of old and new infarctions. The patient with an acute MI and no evidence on physical examination or chest radiographic studies of left ventricular failure has an excellent prognosis, with only a 2% to 5% inhospital mortality rate (Killip class I). The individual with some evidence of pulmonary vascular congestion (e.g., basilar rales, S3, radiographic evidence of pulmonary venous congestion) is classified as Killip class II and has a short-term mortality rate of 10% to 15%. In the patient with overt pulmonary edema evidenced on physical examination or chest radiographic studies, mortality rate is 20% to 30% (Killip class III). Finally, the patient with cardiogenic shock is said to be Killip class IV and has a mortality rate of 50% to 60% even with maximal therapy. In these individuals, infarction is associated with systemic arterial hypotension and diminished peripheral perfusion, as manifested by mental confusion, cold and clammy skin, peripheral cyanosis, and oliguria. Hemodynamically, the systemic arterial systolic pressure is less than 90 mm Hg, the cardiac index is less than 1.8 L/m2 per minute, the systemic arteriolar resistance is greatly increased (>2000 dynes/cm5 per second), and the left ventricular filling pressure is elevated (more than 20 mm Hg) for more than 30 minutes. The reduced systemic arterial pressure further diminishes coronary arterial perfusion pressure, thereby increasing myocardial ischemia. The low cardiac output and systemic arterial pressure induce an intense sympathetic discharge that produces peripheral vasoconstriction, further decreasing tissue perfusion and causing a systemic lactic acidosis, which depresses myocardial function. In response to a reduced cardiac output, the heart rate increases, thereby increasing myocardial oxygen demand. As left ventricular filling pressure rises, subendocardial perfusion is further compromised. In short, the hemodynamic and metabolic consequences of cardiogenic shock cause worsening myocardial ischemic injury, which, in turn, leads to worsening left ventricular dysfunction. A cycle of severe hemodynamic impairment and deteriorating myocardial oxygenation is established. The therapy of the patient with an acute MI and resultant left ventricular dysfunction depends on the extent of such dysfunction. The normotensive individual with symptoms and signs of Killip class II congestive heart failure (i.e., mild orthopnea, basilar rales, S3) usually responds to bed rest, salt restriction, a loop diuretic, and low-dose vasodilator therapy with an ACE inhibitor. Additional therapy with digitalis or other inotropic agents is not usually necessary, nor is invasive hemodynamic monitoring. The management of the patient with more severe heart failure (Killip class III or IV) should be based on a careful assessment of hemodynamic variables obtained with a balloon-tipped flotation catheter in the pulmonary artery and an intra-arterial cannula. Adequate oxygenation should be ensured by continuous pulse oximetry with supplemental oxygen or ventilator support as needed. Placement of a urinary catheter enables the urine output to be assessed accurately, and endotracheal intubation and assisted ventilation may reduce the work of breathing and improve tissue oxygenation. Intravenous furosemide should be administered in an attempt to reduce the pulmonary capillary wedge pressure in the range of 18 to 20 mm Hg; this appears to be the optimal preload in the setting of acute MI. In the normotensive individual, vasodilator therapy

Chapter 9—Coronary Heart Disease with nitroglycerin and oral ACE inhibitors should be instituted to reduce afterload, increase cardiac output, and lower left ventricular filling pressure. The resultant decrease in left ventricular wall stress reduces myocardial oxygen requirements, improves subendocardial perfusion, and helps relieve ischemia. Nitroglycerin should be administered to avoid an excessive reduction in systemic arterial pressure, which may compromise myocardial perfusion, while keeping pulmonary capillary wedge pressure in the range of 18 to 20 mm Hg. The patient with heart failure and hypotension or an inadequate response to diuretics and vasodilators (i.e., cardiac output < 1.8 L/m2 per minute pulmonary capillary wedge pressure > 20 mm Hg) should be treated with intravenous inotropic agents (e.g., dopamine or dobutamine, depending on the systemic arterial pressure). If the patient is only mildly hypotensive, dobutamine is the preferred inotropic agent. Dopamine should be reserved for the patient with more severe hypotension because it may increase pulmonary capillary wedge pressure. In the patient with severe heart failure or cardiogenic shock, a careful search for a potentially correctable cause should be undertaken. Two-dimensional and color Doppler echocardiography, which can rapidly be performed at the bedside, will allow the clinician to determine whether the shock is due to extensive left ventricular dysfunction or a mechanical problem, such as acute mitral regurgitation, acute ventricular septal defect, extensive right ventricular infarction, or a contained rupture of the left ventricular free wall (see “Mechanical Complications”). Patients with shock who are examined within the first few hours of the onset of MI should be considered for immediate reperfusion therapy. Thrombolytic agents are less effective in opening the occluded infarct-related artery in the patient with cardiogenic shock, and these agents have not convincingly exerted a beneficial effect in such patients. Conversely, early coronary revascularization within 12 hours of the onset of cardiogenic shock, accomplished percutaneously or sur gically, has been shown to improve in-hospital and 1-year survival. By reducing afterload and increasing myocardial perfusion pressure, intra-aortic balloon counterpulsation may be effective in stabilizing the patient with cardiogenic shock. Although initial hemodynamic improvement in this setting may be dramatic, balloon counterpulsation alone probably does not improve the poor prognosis associated with car diogenic shock. Rather, counterpulsation should be con sidered a supportive measure in patients with potentially reversible abnormalities before cardiac catheterization, cardiac surgery, or, in some cases, cardiac transplantation. In patients who remain hemodynamically unstable despite pressors and intra-aortic balloon counterpulsation, per cutaneous left ventricular support device implantation should be considered. If these therapies do not improve hemodynamics, a surgical ventricular assist device could be considered.

Right Ventricular Infarction Right ventricular infarction usually occurs in association with inferior MI because the blood supply to both these areas usually comes from the right coronary artery. The presence of a concomitant right ventricular infarction substantially increases the mortality of an inferior MI. Right ventricular

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MI results in the clinical triad of hypotension, clear lungs (i.e., normal pulmonary capillary wedge pressure), and prominent jugular venous distention. In the absence of hemodynamic measurements, right ventricular infarction may be confused with hypovolemia, pulmonary embolism, or cardiac tamponade. In fact, the patient with acute right ventricular failure may have a prominent y descent in the atrial pressure tracing (Fig. 9-10), Kussmaul sign, and pulsus paradoxus, all of which mimic pericardial tamponade. Demonstrating ST-segment elevation in the right precordial leads (e.g., >0.1 mV elevation in V4R) confirms the diagnosis of right ventricular infarction. For this reason, a right-sided precordial ECG should be obtained in all patients with inferior MI. The treatment of hypotension in the patient with right ventricular infarction often requires rapid intravascular volume repletion (with a goal right atrial pressure of 12 to 15 mm Hg) and inotropic agents (e.g., dobutamine). A balloon-tipped flotation catheter in the pulmonary artery and an intra-arterial cannula should be used for hemodynamic monitoring. Diuretic and vasodilator (e.g., nitroglycerin) therapy should be avoided because they may provoke hypotension in this setting. If the patient can be supported during the first few days of hemodynamic instability, considerable improvement in right ventricular function often occurs.

ECG

RADIAL ARTERIAL PRESSURE

100 50 0

PULMONARY ARTERY PRESSURE

RIGHT ATRIAL PRESSURE

20 10 0 10 5 0

Figure 9-10 Electrocardiographic (ECG), arterial, and SwanGanz bedside catheter recordings in a patient with right ventricular infarction. Hypotension is present, and cardiac output, estimated by thermodilution (not shown), is reduced. The pulmonary arterial pressures are normal, whereas the right atrial pressure is elevated, and it demonstrates a prominent y descent.

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Mechanical Complications Mechanical complications of acute MI include papillary muscle rupture, ventricular septal defect, and ventricular free-wall rupture. Patients with these complications frequently experience hemodynamic collapse 3 to 5 days after acute MI. These complications are associated with high mortality rates; they account for about 15% of the mortality from acute MI. Successful immediate reperfusion therapy has reduced the appearance of these complications. Patients with late or unsuccessful reperfusion therapy are at higher risk for these mechanical complications. Papillary muscle rupture results in acute mitral regurgitation. The resultant sudden increase in left atrial volume causes a significantly elevated left atrial pressure, with resultant pulmonary edema. Papillary muscle rupture occurs most commonly with inferior MI because the posteromedial papillary muscle usually has a single source of blood supply from the right coronary artery. Conversely, the anterolateral papillary muscle has a dual blood supply. A loud, apical holosystolic murmur is usually audible, although an occasional patient with severe mitral regurgitation has no audible murmur. The diagnosis may be rapidly confirmed with transthoracic echocardiography or right-heart ventricular catheterization, with the latter demonstrating large v waves in the pulmonary capillary wedge tracing in the absence of an oxygen step-up in the right ventricle. An acute ventricular septal defect may occur after anterior or inferior MI. On physical examination, a harsh holosys tolic murmur is audible at the left lower sternal border, which may be difficult to differentiate from acute mitral regurgitation; this murmur is often accompanied by a palpable thrill. The diagnosis can be confirmed by obtaining blood samples from each of the cardiac chambers during right heart ventricular catheterization and by demonstrating a higher oxygen saturation in the samples obtained from the right ventricle or pulmonary artery compared with those obtained from the right atrium (e.g., oxygen step-up). Specifically, an increase in oxygen saturation of more than 6% between the right atrium and pulmonary artery strongly suggests the presence of a ventricular septal defect with concomitant left-to-right shunting. Doppler echocardiography also allows visualization of left-to-right shunting of blood through the ventricular septal defect. Treatment of acute papillary muscle rupture or ventricular septal defect includes inotropic agents, vasodilators, and intra-aortic balloon counterpulsation. These temporizing measures help prepare the patient for urgent cardiac surgery to repair the ventricular septal defect or replace the mitral valve. Free-wall rupture of the left ventricle almost always results in hemopericardium, cardiac tamponade, and electromechanical dissociation. Survival is uncommon and depends on prompt recognition and emergent surgical repair. In an occasional patient, a pseudoaneurysm or false aneurysm develops when free-wall rupture occurs, so that the rupture is confined by the adherent pericardium, organized thrombus, and hematoma. Because the wall of the pseudoaneurysm contains no myocardium, it may rupture at a later date. The pseudoaneurysm maintains continuity with the left ventricular cavity through a narrow connecting orifice (e.g., neck). In contrast, a true aneurysm represents an area of infarcted myocardium that has become thinned and dilated

through a process of ventricular remodeling. True aneurysms have a wide orifice or neck, their walls always contain some myocardial elements, and they rarely rupture. Pseudoaneurysms should undergo prompt surgical resection because of the risk for rupture. Conversely, a true aneurysm does not require urgent surgical resection. Medical treatment of post-MI aneurysms includes aggressive heart failure management with ACE inhibitors, β blockers, aldosterone inhibitors for those with class III or IV heart failure, and consideration of anticoagulant therapy. Those undergoing subsequent CABG and those with aneurysm-related chest pain may be considered for aneurysmectomy.

SECONDARY PREVENTION OF ACUTE CORONARY SYNDROME Secondary prevention therapies are a critical component of the management of all patients with acute coronary syndrome. About 70% of coronary heart disease deaths and 50% of MIs occur in patients with a prior history of coronary artery disease. Secondary prevention therapies in patients recovering from acute coronary syndrome represent a major opportunity to reduce cardiovascular morbidity and mortality. Before hospital discharge, patients should be educated regarding adherence to the recommended lifestyle changes and pharmacologic therapies. Patients and their families should receive discharge instructions about recognizing acute cardiac symptoms and appropriate actions to take in order to ensure early evaluation and treatment should symptoms recur. Family members should be advised about cardiopulmonary resuscitation and automatic external defibrillator (AED) training programs. Lipid management involves dietary therapy that is low in saturated fat and cholesterol (10%). Other clinical factors that increase the risk for stroke in patients with AF include prior stroke, diabetes, hypertension, heart failure, left atrial enlargement, and increasing age. No difference in stroke rate occurs between paroxysmal and chronic AF. Restoration of normal sinus rhythm has not been shown to reduce the risk for stroke. In fact, in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, a trend toward a higher incidence of stroke in patients randomized to rhythm control was found when compared with rate control, albeit not statistically significant. This trend was most likely caused by the decreased use of warfarin in the rhythm control group. Therefore, any patient with paroxysmal, persistent, or permanent AF who does not have a contraindication to anticoagulation should be treated with warfarin therapy with a target international normalized ratio between 2 and 3. Rate Control Rate control in AF is important for several reasons. It has been shown to improve symptoms and quality of life. Symptoms and hemodynamic compromise are increased at faster ventricular rates, and the tachycardic response may induce ischemia in patients with coronary artery disease. In addition, the poorly controlled heart rate may result in the development of progressive ventricular dysfunction. The heart rate can usually be controlled with digoxin, β blockers, or calcium channel blockers. In rare instances, the ventricular rate cannot be controlled by pharmacologic means, and catheter ablation of the AV node and permanent pacemaker implantation are necessary for adequate heart rate control. Occasionally, patients exhibit AF and a relatively slow ventricular rate in the absence of rate-lowering medications. This circumstance usually reflects significant underlying conduction system disease that also often involves the sinus node. Rhythm Control Rhythm control has several advantages, including (1) abolition of symptoms, (2) halting atrial enlargement (an independent predictor of stroke), and (3) improvement of left

Chapter 10—Cardiac Arrhythmias ventricular function and exercise capacity. The main disadvantage is subjecting patients to a drug therapy or procedure that might be associated with complications. As stated before, rhythm control has not been shown to reduce the risk for stroke or to have an impact on mortality when compared with rate control. Therefore, rhythm control should be attempted in patients who are symptomatic despite rate control and in those who have left ventricular dysfunction. When AF is associated with hemodynamic compromise, electrical cardioversion (with 100 to 360 joules) is the treatment of choice. In hemodynamically stable patients with less than 48 hours of AF, the risk for thromboembolism is low, and pharmacologic or electrical cardioversion can be attempted without the need for 3 weeks of anticoagulation (see later discussion). Patients with more than 48 hours of AF, or in whom the duration of the arrhythmia is unknown, are at increased risk for atrial thrombi and should be treated with anticoagulation for at least 3 weeks before an attempt at cardioversion. An alternative approach is to perform a transesophageal echocardiogram; if atrial thrombi are not present, cardioversion can be safely performed. Anticoagulation should be continued for at least 4 weeks after successful cardioversion because effective atrial contraction may be slow to return. The options for maintaining rhythm control include (1) pharmacologic therapy, (2) catheter ablation, and (3) surgical Maze procedure. The class IA (quinidine, procainamide, and disopyramide), class IC (propafenone and flecainide), and class III (sotalol and amiodarone) agents are effective in restoring sinus rhythm and for long-term maintenance therapy. However, the benefits of such therapy must be weighed against the risks for toxicity with these agents, and the probability of maintaining sinus rhythm must be taken into account. The preferred choice of drug therapy for the maintenance of sinus rhythm in patients with paroxysmal and persistent AF, based on the most recent American College of Cardiology/American Heart Association guidelines, is provided in Figure 10-7. Radiofrequency

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ablation of the ostia of the pulmonary veins or electrical isolation of the pulmonary veins from the left atrium is a procedure that should be reserved to symptomatic patients who have failed drug therapy. Ablation therapy frequently abolishes the arrhythmia, improving symptoms and, at times, left ventricular function in patients with baseline congestive heart failure. The surgical maze procedure involves making surgical lesions in the atria that interrupt reentrant circuits and may restore sinus rhythm in more than 90% of patients. This procedure is usually performed in conjunction with mitral valve surgery.

ATRIOVENTRICULAR NODAL (JUNCTIONAL) RHYTHM DISTURBANCES Atrioventricular Nodal Reentrant Tachycardia Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common type of paroxysmal SVT and is characterized by the sudden onset and termination of a regular narrow QRS complex tachycardia at rates of 150 to 250 beats/minute (Fig. 10-8A). A wide QRS complex may occur if aberrant conduction occurs in the His-Purkinje system. These rhythms may occur at any age, are somewhat more common in women than men, may occur in the absence of organic heart disease, may be short lived or sustained, and may produce palpitations, chest pain, dyspnea, and presyncope. The substrate for this tachycardia is dual AV node pathways with different effective refractory period (ERP): a fast pathway with a longer ERP and a slow pathway with a shorter ERP. Whether these pathways are exclusively intra nodal or not remains controversial, but catheter ablation studies of these pathways have revealed distinct atrial insertion sites, with the fast pathway inserting anteriorly near the His bundle and the slow pathway posteriorly near the coronary sinus ostium.

Heart disease

Yes

No (or minimal)

Flecainide Propafenone Sotalol

Heart failure

CAD

Hypertension

Amiodarone Dofetilide

Sotalol Dofetilide

LVH ≥1.4 cm

No

Yes Amiodarone Dofetilide

Catheter ablation

Catheter ablation

Amiodarone

Flecainide Propafenone Sotalol Amiodarone

Figure 10-7 Drug therapy to maintain sinus rhythm in patients with recurrent paroxysmal or persistent atrial fibrillation. CAD, coronary artery disease; LVH, left ventricular hypertrophy.

Catheter ablation

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A

B

C

D

E

F Figure 10-8 Atrioventricular (AV) nodal (junctional) rhythm disturbances. A, AV nodal reentrant tachycardia at a rate of 185 beats/ minute. The retrograde P waves are hidden in the QRS complexes. B, Automatic junctional tachycardia. Note the presence of AV dissociation during tachycardia. The P waves (arrows) are dissociated from the QRS complexes. C, Normal sinus rhythm in a patient with Wolff-Parkinson-White (WPW) syndrome. Note the short PR interval (5 cm for all others Aortic arch >5.5 cm Descending thoracic aorta >5 cm Abdominal aorta >5.5 cm Iliac aneurysm >3 cm

palpable but above the umbilicus. Hypotension and acute abdominal pain should prompt consideration of aneurysm rupture, which requires emergent operative repair. Duplex ultrasonography is an accurate and reliable diagnostic tool for abdominal aortic and iliac aneurysms. Routine screening for AAA with ultrasonography is recommended for all men between the ages of 65 and 75 years or men above the age of 60 with family history of AAA among firstdegree relatives. Such screening has a proven mortality benefit. CT and MR angiography allow visualization of the thoracic and abdominal aorta as well as the iliac arteries and its branches (Fig. 13-2). Medical treatment for aortic aneurysm includes smoking cessation, tight BP control, and cholesterol reduction. β-Adrenergic blockade reduces the rate of aortic root enlargement in patients with Marfan syndrome but has not proved beneficial in patients with AAA from other causes. Patients with large aneurysms or rapid aneurysm expansion regardless of the size should undergo aneurysm repair (Table 13-2). Elective AAA repair carries a

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peri-operative mortality rate of 2% to 6%. Furthermore, a large randomized study failed to demonstrate any benefit of surgery in patients with aneurysms 4 to 5.5 cm in diameter. For these reasons, patients with small aortic aneurysms should be treated medically with close monitoring of aneurysm size with periodic imaging studies every 6 to 12 months (see Table 13-2). Percutaneous endovascular aneurysm repair (EVAR) is an alternative method to open surgical repair for treatment of AAA. EVAR offers lower perioperative death than surgical repair, but long-term survival rates are not different from surgery. EVAR has not been shown to improve mortality in patients with multiple co-morbidities, who are considered to be unfit for surgery, when compared with conservative management. Therefore, it should be offered only to selected patients with symptoms from compression of adjacent organs or vascular complications.

Aortic Dissection In aortic dissection, the intimal layer is torn from the aortic wall, leading to the formation of a false lumen in parallel with the true lumen. Risk factors include hypertension, cocaine use, trauma, hereditary connective tissue disease (e.g., Marfan syndrome, Ehlers-Danlos syndrome), vasculitis (e.g., Takayasu arteritis, giant cell arteritis), Behçet disease, bicuspid aortic valve, and aortic coarctation. Aortic dissection can be classified as types A and B (Stanford system). Type A dissection involves the ascending aorta, whereas type B dissection involves the distal aorta. The DeBakey system subdivides aortic dissection into three subtypes: types I, II, and III. Type I dissection involves the entire aorta, whereas type II involves only the ascending aorta, and type III involves only the descending aorta. Aortic dissection involving the ascending aorta carries a high mortality rate of 1% to 2% per hour during the first 24 to 48 hours. Patients usually develop acute onset of severe chest or back pain. Abdominal pain, syncope, and stroke are common. Retrograde propagation of the dissection can cause pericardial tamponade or coronary artery dissection with acute myocardial infarction. Dissection involving the aortic valve causes acute severe aortic insufficiency with acute pulmonary edema. The dissection plane may propagate in an antegrade direction to compromise flow in the carotid and subclavian arteries, producing a stroke or acute upper limb ischemia. Patients with distal (type B) aortic dissection exhibit acute onset of back pain or chest pain often accompanied by lower extremity ischemia and ischemic neuropathy. The physical findings include pulse deficits, neurologic deficits, or a diastolic murmur of aortic regurgitation. However, acute aortic regurgitation into an unprepared ventricle produces only a short, soft diastolic murmur that is often missed. The widened pulse pressure and associated physical findings of chronic aortic regurgitation are absent, and the clinical picture is that of an acutely ill patient with tachypnea, tachycardia, and a narrow pulse pressure. Hypotension, jugular venous distention, and pulsus paradoxus should prompt the diagnosis of pericardial tamponade. Transesophageal echocardiography, MR angiography, or CT angiography confirms the diagnosis by demonstrating an intimal flap that separates the true lumen from the false lumen (Fig. 13-3). Type A aortic dissection is uniformly fatal without emergent surgical repair. With surgery, mortality is reduced to 10% at

Figure 13-3 Computed tomographic angiogram of the aorta shows type B aortic dissection. The intimal flap (arrow) separates the true lumen (T) from the false lumen (F) and compromises blood flow to the right kidney, causing renal atrophy and cortical thinning. (Image courtesy of Bart Domatch, MD, Radiology Department, University of Texas Southwestern Medical Center, Dallas, Texas.)

24 hours and 20% at 30 days. Patients with type B aortic dissection should be treated medically because 1-year survival is higher with medical therapy than it is with surgery (75% versus 50%). However, surgery is indicated if type B dissection compromises blood flow to the legs, kidneys, or other viscera. Tight control of BP is essential because aortic aneurysm develops in 30% to 50% of patients with type B aortic dissection studied for 4 years.

Penetrating Aortic Ulcers and Intramural Hematoma Penetrating aortic ulcers and intramural hematomas exhibit chest pain that is indistinguishable from that of aortic dissection. In contrast to aortic dissection, however, the pathologic condition is localized. No identifiable intimal flap and thus no branch vessel occlusion are produced. Disruption of the internal elastic lamina produces aortic ulcers that erode into the medial wall and protrude into the surrounding structures. Rupture of the vasa vasorum causes formation of localized hematoma underneath the adventitia with resultant asymmetrical thickening of the aortic wall. Patients with either condition typically are older than those with aortic dissection, have a larger aortic size, and have a higher prevalence of AAA. Aortic rupture is the major complication of both penetrating ulcers and intramural hematomas, particularly with those aneurysms located in the ascending aorta. The diagnosis is made with invasive angiography, CT angiography, or MR angiography (Fig. 13-4). Surgical intervention should be considered for ulcers and hematomas of the ascending aorta, deeply penetrating ulcers, or severely bulging hematomas, irrespective of their location. Ulcers and hematomas of the descending aorta may be managed successfully with β-adrenergic blockade and tight control of BP.

Chapter 13—Vascular Diseases and Hypertension

Figure 13-4 Computed tomographic angiogram of the descending thoracic aorta shows a large penetrating aortic ulcer above the diaphragm (arrow). (Image courtesy of Bart Domatch, MD, Radiology Department, University of Texas Southwestern Medical Center, Dallas, Texas.)

Other Arterial Diseases Buerger disease is a nonatherosclerotic disease of the arteries, veins, and nerves of the arms and legs affecting mostly young men before the age of 45 years. The cause is unknown, but all patients have a history of heavy tobacco addiction. The presenting symptom is claudication of the feet, legs, hands, or arms. Multiple-limb involvement and superficial thrombophlebitis are common. The C-reactive protein and Westergren sedimentation rate typically are normal, and a search for serologic markers for connective tissue disease (e.g., antinuclear antibody or rheumatoid factor, antiphospholipid antibody) is negative. The diagnosis is usually based on the typical clinical presentation. If the presentation is atypical, biopsy may be needed to make the diagnosis. The histologic hallmark is inflammatory intramural thrombi within the arteries and veins with sparing of internal elastic lamina and other arterial wall structures. The most effective treatment of Buerger disease is complete tobacco abstinence. The prostacyclin analogue iloprost constitutes adjunctive therapy to reduce limb ischemia and improve wound healing. Raynaud phenomenon is a vasospastic disease of the small arteries of mainly the fingers and toes. Primary (idiopathic) Raynaud phenomenon occurs in the absence of underlying disorders. Secondary Raynaud phenomenon occurs in association with connective tissue diseases (e.g., scleroderma, polymyositis, rheumatoid arthritis, systemic lupus erythematosus) as well as with repeated mild physical trauma (e.g., use of jack hammers), certain drugs (e.g., antineo plastic chemotherapeutic agents, interferon, monoaminereuptake inhibitors such as tricyclic antidepressants, serotonin agonists), and Buerger disease. Patients usually complain of recurrent episodes of digital ischemia, with a characteristic white-blue-red color sequence. Pallor is followed by cyanosis if ischemia is prolonged and then by erythema (reactive hyperemia) when the episode resolves. Episodes are precipitated by cold temperature or emotional stress. Physical examination can be entirely normal between

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attacks with normal radial, ulnar, and pedal pulses. Some patients may have digital ulcers or thickening of fat pad (sclerodactyly). Patients should be instructed to avoid cold temperatures and dress warmly. Calcium channel blockers (CCBs) reduce the frequency and severity of vasospastic episodes. Giant cell arteritis is an immune-mediated vasculitis predominantly involving medium-sized and large arteries such as the subclavian artery, axillary artery, and aorta of the older adult with a strong male predominance. About 40% of patients with giant cell arteritis also have polymyalgia rheumatica, a syndrome characterized by severe stiffness and pain originating in the muscles of the shoulders and pelvic girdle. Patients may exhibit headache from temporal arteritis, jaw claudication from ischemia of the masseter muscles, or visual loss from involvement of ophthalmic artery. Chest pain suggests the co-existence of aortic aneurysm or dissection. Physical findings include low-grade fever, scalp tenderness in the temporal area, pale and edematous fundi, or a diastolic murmur of aortic regurgitation. BP difference of more than 15 mm Hg between arms suggests subclavian artery stenosis. Laboratory findings include significantly elevated C-reactive protein and Westergren sedimentation rate plus anemia. The diagnosis is confirmed by histologic examination of the arterial tissue (frequently from temporal artery biopsy), showing infiltration of lymphocytes and macrophages (i.e., giant cells) in all layers of the vascular wall. High-dose corticosteroids are highly effective. To minimize complications from long-term corticosteroid administration, the steroid dose should be tapered to find the lowest dose needed to suppress symptoms, which often wane. Every attempt should be made to discontinue corticosteroids over time. Takayasu arteritis is an idiopathic granulomatous vasculitis of the aorta, its main branches, and the pulmonary artery. This condition is particularly common in young women of Asian descent, but it also occurs in occidental women and men. The inflammatory process in the vascular wall can lead to stenosis and aneurysm formation. Hypertension, as a result of renal artery stenosis or aortic coarctation, is the most common manifestation and is present in as many as 80% of affected individuals. Because the vascular involvement is so widespread, patients may have symptoms and signs of coronary ischemia, congestive heart failure, stroke, vertebrobasilar insufficiency, or intermittent claudication. Physical findings include bruits over the subclavian arteries or aorta as well as diminished brachial pulses and thus a low brachial artery BP. The diagnosis is based primarily on this clinical presentation. First-line treatment is with corticosteroids. Other immunosuppressive agents such as methotrexate or cyclophosphamide are often added to prevent disease progression and relapse. Immunosuppressive therapy does not cause regression of preexisting vascular stenoses or aneurysms. For this reason, percutaneous or surgical revascularization is usually required. Arteriovenous (AV) fistulas are abnormal vascular communications that shunt blood flow from the arterial system directly into the venous system, bypassing the capillary beds that normally ensure optimal tissue perfusion and nutrient exchange. AV fistulas may be congenital, as in AV malformation (AVM), or acquired. The main causes of acquired AV fistula are penetrating trauma (e.g., gunshot, knife

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wound) and surgically created shunts for hemodialysis access. Patients may exhibit a pulsatile mass, symptoms related to compression of an adjacent organ, or bleeding from spontaneous rupture of an AVM. Systolic and diastolic bruits or thrills may be detectable over the fistula or AVM. An AVM in skeletal muscle may lead to bone malformation or a pathologic fracture, whereas AVM in the brain may result in neurologic deficits or seizures. High-output heart failure is another complication from a large AVM or fistula. MR angiography, CT angiography, or conventional angiography confirms the diagnosis. Depending on the size and location of the AVM, treatment options include surgical resection, transcatheter embolization, or pulse laser irradiation. Patients with acquired AV fistulas from trauma usually need surgical closure.

Pulmonary Vascular Disease Pulmonary hypertension is characterized by elevated mean pulmonary pressure of greater than 25 mm Hg at rest or greater than 30 mm Hg during exercise. The many causes of pulmonary hypertension are summarized in Table 13-3. Patients with pulmonary hypertension have not only an elevated pulmonary arterial pressure but also a low cardiac output, causing symptoms of exertional dyspnea, fatigue, and syncope. Pulmonary capillary wedge pressure is usually

Table 13-3 Classification of Pulmonary Hypertension Category 1: Pulmonary Arterial Hypertension Primary pulmonary hypertension or idiopathic pulmonary hypertension: Sporadic Familial PPH associated with: Connective tissue disease Congenital heart disease Portal hypertension Human immunodeficiency viral infection Drugs and toxins: Anorexigens Cocaine Category 2: Pulmonary Venous Hypertension Left ventricular heart failure Left ventricular valvular heart disease Category 3: Pulmonary Hypertension associated with Chronic Respiratory Disease or Hypoxemia Chronic obstructive pulmonary disease Obstructive sleep apnea Category 4: Pulmonary Hypertension associated with Chronic Venous Thromboembolism Left ventricular valvular heart disease Category 5: Pulmonary Hypertension Due to Miscellaneous Disorders Directly Affecting the Pulmonary Vasculature Sarcoidosis Histiocytosis X Compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

normal except in patients with pulmonary venous hypertension and congenital heart disease.

PULMONARY ARTERIAL HYPERTENSION Pulmonary arterial hypertension (PAH) is caused by a combination of pulmonary vasoconstriction, endothelial cell or smooth muscle proliferation, intimal fibrosis, and thrombosis in the pulmonary capillaries and arterioles. PAH is either idiopathic (primary pulmonary hypertension [PPH]) or secondary to connective tissue disease, congenital heart disease, portal hypertension, or human immunodeficiency virus (HIV) infection as well as anorexigenic drugs or toxins. Connective tissue diseases, particularly scleroderma, are the most common secondary causes of PAH. Patients with mild PAH can be asymptomatic, but patients with more advanced disease complain of dyspnea, chest pain, syncope, or presyncope. Physical findings include a left parasternal lift, loud pulmonary component of the second heart sound, murmur of tricuspid or pulmonic regurgitation, hepatomegaly, peripheral edema, or ascites. Associated ECG abnormalities indicate right ventricular hypertrophy, right atrial enlargement, or right axis deviation. Echocardiography provides important information about the severity of the pulmonary hypertension (i.e., estimated pulmonary artery pressure, right ventricular dimensions and function) and its potential causes (e.g., left ventricular failure, valvular lesions, congenital heart disease with left-to-right shunts). ) Pulmonary function tests, ventilation-perfusion ( V Q lung scans, polysomnography or overnight oximetry, autoantibody tests, HIV serology, and liver function tests also should be performed to determine other potential causes. Right ventricular catheterization should be performed in all patients with suggested PAH. Under basal conditions in the catheterization laboratory, an elevated mean pulmonary artery pressure exceeding 25 mm Hg, a pulmonary capillary wedge pressure below 15 mm Hg, and a pulmonary vascular resistance exceeding 3 units confirm the diagnosis. Acute vasodilator drug challenge should be performed during right ventricular catheterization to guide appropriate treatment. Without treatment, the prognosis of PAH is poor, with a median survival of less than 3 years. Patients with severe symptoms should be treated with prostacyclin or epoprostenol (an intravenous prostacyclin analogue) because of their proven efficacy in improving exercise capacity, quality of life, and survival. Other prostacyclin analogues, such as treprostinil and iloprost, are also effective in reducing pulmonary artery pressure and improving exercise capacity. Other classes of drugs approved for treatment of PAH include endothelin receptor blockers and phosphodi esterase-5 inhibitors. Oral CCBs are indicated for the small subset of patients with mild to moderate symptoms who demonstrate significant reduction in pulmonary pressure with acute CCB challenge. Supplemental home oxygen is indicated for all patients with hypoxemia. Higher elevations exacerbate hypoxemia, and relocation to sea level improves symptoms. Oral anticoagulation is recommended for all patients with PAH. Diuretics should be prescribed for patients with peripheral edema or hepatic congestion. Lung transplantation is recommended only for patients in whom severe symptoms occur despite intensive medical therapy.


Venous Thromboembolic Disease Venous thromboembolism (VTE) encompasses both deep vein thrombosis (DVT) and pulmonary embolism (PE). Among the adult U.S. population, the overall combined annual incidence is as high as 1 new case per 1000 persons. The incidence of VTE is higher in men than in women and higher in African Americans and whites than in Asians and Hispanics. More than 150 years ago, Dr. Rudolf Virchow recognized three predisposing factors: (1) endothelial damage, (2) venous stasis, and (3) hypercoagulation (Virchow triad). Endothelial damage is common with surgery or trauma, venous stasis is common with prolonged bed rest or immobilization (leg cast), and hypercoagulation is common with cancer. Trousseau syndrome consists of migratory thrombophlebitis with noninfectious vegetations on the heart valves (marantic endocarditis) typically in the setting of mucin-secreting adenocarcinoma. Dr. Trousseau, a pathologist, diagnosed his own pancreatic carcinoma on the basis of the association that now bears his name. Hypercoagulable states include hereditary diseases such as deficiencies in antithrombin III, protein C, or protein S; mutation in factor V gene (factor V Leiden) or factor II gene (prothrombin G20210A); and hyperhomocysteinemia. However, a thorough search for identifiable risk factors will come up negative in 25% to 50% of patients with VTE.

DEEP VEIN THROMBOSIS Most DVT starts in the calf veins. Without treatment, 15% to 30% of these clots propagate to the proximal calf veins. The risk for a subsequent PE is much higher with proximal DVT than those confined to the distal calf vessels (40% to 50% versus 5% to 10%, respectively). Involvement of the upper extremities is much less common, but subclavian and axillary vein thrombosis also can lead to PE in as many as 30% of affected individuals. The same risk factors that cause lower extremity DVT also cause upper extremity DVT. In addition, other specific causes of upper extremity DVT include traumatic damage of the vessel intima from heavy exertion such as rowing, wrestling, or weight lifting (PagetSchroetter syndrome); from extrinsic compression at the level of thoracic inlet (thoracic outlet obstruction); or from insertion of central venous catheters or pacemakers. Pain and swelling are the major complaints from patients with DVT; however, a large number of patients with DVT are asymptomatic, particularly if the DVT is restricted to the calf. Patients with upper extremity DVT can develop the superior vena caval syndrome of facial swelling, blurred vision, and dyspnea. Thoracic outlet obstruction can compress the brachial plexus leading to unilateral arm pain associated with hand weakness. Physical examination frequently reveals tenderness, erythema, warmth, and swelling below the site of thrombosis. Pain with dorsiflexion of the foot (Homan sign) may be present, but the low sensitivity and the low specificity limit its usefulness in the diagnosis of lower extremity DVT. A palpable tender cord, dilated superficial veins, and low-grade fever occur in some patients. Upper extremity DVT can cause brachial plexus tenderness in the supraclavicular fossa and atrophic hand muscles. For

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patients with probable thoracic outlet obstruction, several provocative tests should be performed. Adson test is positive if the radial pulses weaken during inspiration and during extension of the arm of the affected side while rotating the head to the same side. Wright test is positive if the radial pulses become weaker and painful symptoms are reproduced while abducting the shoulder of the affected side with the humerus externally rotated. The laboratory diagnosis of DVT includes measurement of D-dimers, which are fibrin degradation products. D-dimer elevation is a highly sensitive indicator of DVT that can be performed rapidly in the emergency department. In a patient in whom the index of probability is low, a negative D-dimer test effectively excludes the diagnosis of DVT. However, the test is not specific and can be elevated in many other conditions frequently encountered in hospitalized patients (e.g., inflammation, recent surgery, malignancy). Duplex ultrasonography can be used to demonstrate the presence of a blood clot or noncompressibility of the affected veins proximal to the site of occlusion. Duplex ultrasonography has greater sensitivity in detecting proximal DVT (90% to 100%) than distal DVT (40% to 90%) of the lower extremities. With upper extremity DVT, acoustic shadowing of the clavicle may obscure detection of thrombosis in subclavian vein segments. MR angiography is particularly helpful in making the diagnosis of upper extremity DVT and pelvic vein thrombosis. Contrast venography is the conventional gold standard test, but it is invasive and technically difficult in patients with edematous extremities. Therefore, invasive venography should be reserved for patients in whom the clinical suggestion is high, despite negative or inconclusive results from noninvasive imaging. Patients with proximal lower extremity DVT and those with upper extremity DVT should be treated initially with subcutaneous low-molecular-weight heparin (LMWH), intravenous or subcutaneous unfractionated heparin (UFH), or subcutaneous selective factor Xa inhibitor fondaparinux to prevent thrombus propagation and to maintain the patency of venous collaterals. Intravenous UFH should be given as a bolus, followed by continuous infusion to maintain an activated partial thromboplastin time of at least 1.5 times the control value. LMWH and fondaparinux has a longer half-life than UFH and can be given once or twice daily with similar efficacy. Oral warfarin should be initiated together with LMWH, UFH, or fondaparinux without delay and titrated until the international normalized ratio (INR) reaches a value between 2 and 3. When DVT is confined to the calf, the risk for PE is low, and the risk-to-benefit ratio of anticoagulation remains controversial. When upper extremity DVT occurs in young patients who are otherwise healthy, two invasive approaches to thrombus removal should be considered: (1) infusion of a fibrinolytic drug through a catheter inserted directly into the affected vein, or (2) mechanical fragmentation of the thrombus through catheter-based technology. The purpose of these invasive procedures is to prevent or minimize the postthrombotic syndrome, which includes chronic arm pain, swelling, hyperpigmentation, and ulceration from residual venous obstruction. Catheter-based placement of a filter in the inferior vena cava should be considered for patients with proximal DVT who either have an absolute contraindication to anticoagula-

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tion or develop recurrent PE despite an adequate trial of anticoagulation. Vena cava filters are effective in reducing the incidence of PE, but they increase the risk for recurrent DVT. Some proximal or distal migration of the filter occurs in up to 50% of cases; however, clinically evident filter embolization is limited to case reports.

PULMONARY EMBOLISM PE occurs when a thrombus dislodges from the deep veins of the upper or lower extremities. Pulmonary vascular resistance and pulmonary arterial pressure increase from two mechanisms: (1) anatomic reduction in cross-sectional area of the pulmonary vascular bed, and (2) functional hypoxiainduced pulmonary vasoconstriction. The pressure overload on the right ventricle can lead to dilation, hypokinesis, and tricuspid regurgitation. When severe, elevated right ventricular end-diastolic pressure can compress the right coronary artery, causing subendocardial ischemia. In acute PE, areas of lung tissue are ventilated but underperfused. This mismatch and the resultant redistribution of pulmoV Q nary blood flow from obstructed pulmonary artery to other cause arterial hypoxemia. In lung regions with lower V Q patients with a patent foramen ovale, hypoxemia worsens when the sudden elevation in right atrial pressure causes right-to-left shunting across the foramen. The classic symptoms of acute PE are the sudden onset of dyspnea and pleuritic chest pain. Additional symptoms include anginal chest pain from right ventricular ischemia, hemoptysis from pulmonary infarction, and syncope or presyncope from massive PE with acute right ventricular failure (cor pulmonale). The most common physical findings are tachypnea and tachycardia. Additional physical findings include a right ventricular lift, inspiratory crackles, a loud pulmonary component of the second sound, expiratory wheezing, and a pleural rub. Symptoms and signs of proximal DVT are present in 10% to 20% of patients. Arterial blood gas analysis often reveals hypoxemia, respiratory alkalosis, and a high alveolar-to-arterial oxygen tension gradient. However, normal arterial blood gas values do not exclude the diagnosis. The most common finding with ECG analysis is sinus tachycardia. Atrial fibrillation, premature atrial contraction, and supraventricular tachycardia are less common. Other ECG changes suggest acute right ventricular strain. These include the S1-Q3-T3 pattern, a new right bundle branch block or right axis deviation, and P-wave pulmonale. However, these findings are present in only 30% of patients with even massive PE. Common but nonspecific abnormalities with chest radiographic studies include atelectasis, pleural effusion, and pulmonary infiltrates. Less common but more specific radiographic findings include Hampton hump (i.e., wedge-shaped infiltrate in the peripheral lung field), which is indicative of pulmonary infarction, and Westermark sign (decreased vascularity). The plasma D-dimer test is elevated in most patients with PE as a result of activation of the endogenous fibrinolytic system, which is not sufficient to dissolve the clot. Commercially available D-dimer assays have a high sensitivity and negative predictive value but low specificity. Therefore, a normal D-dimer test effectively excludes the diagnosis of PE in patients in whom the clinical suggestion is low or intermediate. However, it should not be used to screen patients with a high

Figure 13-5 Spiral chest computed tomographic angiogram shows a large thrombus in the right main pulmonary artery (arrow). (Image provided by Michael Landay, MD, Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas.)

index of suspicion because of low negative predictive value. Elevated levels of cardiac troponin I and troponin T and other markers of myocardial injury can be found in patients with PE and are indicative of right ventricular dysfunction and a poor prognosis. In patients with suggested PE, a completely normal V Q scan effectively excludes the diagnosis without further test scans are interpreted ing. However, less than 10% of V Q as definitively normal. In patients in whom a moderate or high level of clinical probability of PE exists, a high scan has a diagnostic accuracy of 90% to probability V Q 100%; however, a low or intermediate probability scan is no more helpful than a coin flip. More recently, multidetector CT angiography has become the imaging modality of choice in patients with acute PE because of its excellent visualization of the pulmonary artery (Fig. 13-5). The resolution of 1 mm or less rivals that of conventional invasive angiography. The speed of the newer-generation scanners allows acquisition of all images within a single breath-hold, avoiding respiratory motion artifacts. The overall negative predictive value of multidetector CT angiography exceeds 99%. A negative CT scan excludes the diagnosis of PE and eliminates the need for further diagnostic testing. CT also permits detection of other pathologic conditions involving the lung parenchyma, pleura, and mediastinal structures. Such pathologic findings may mimic PE and constitute alternative causes of chest pain and dyspnea. Multidetector CT angiography is not yet available at all centers. The requirement for intravenous injection of iodinated contrast material restricts applicability to those without a history of kidney disease or an allergic reaction to contrast dye. Figure 13-6 presents an algorithm for the work-up of PE based on current evidence. Echocardiography may directly detect thrombi in the right atrium, right ventricle, or pulmonary artery or indirectly demonstrate right ventricular dysfunction, signifying presence of hemodynamically significant emboli. Therefore, it is helpful in diagnosis of PE in patients with hypotension or shock, particularly when multidetector CT are not immediately available. Invasive pulmonary angiography should

Chapter 13—Vascular Diseases and Hypertension Pre-test Probability Score Clinical signs of DVT Heart rate >100 beats/min Recent surgery or immobilization Previous DVT or PE Hemoptysis Cancer PE more likely than alternative diagnosis

3 1.5 1.5 1.5 1 1 3

Score 30 mg/g New elevation in serum creatinine, significant elevation in serum creatinine with initiation of ACEI or ARBs, refractory hypertension, flash pulmonary edema, abdominal bruit Arm pulses > leg pulses, arm BP > leg BP, chest bruits, rib notching on chest radiograph Hypokalemia, refractory hypertension

Truncal obesity, wide and blanching purple striae, muscle weakness Spells of paroxysmal hypertension, palpitations, perspiration, pallor, pain in the head Diabetes Loud snoring, daytime somnolence, obesity, large neck

MR or CT angiography, invasive angiogram Chest MRI or CT, aortogram Plasma renin and aldosterone, 24-hr urine potassium, 24-hr urine aldosterone and potassium after salt loading, adrenal CT, adrenal vein sampling 24-hr urine cortisol, dexamethasone suppression test, adrenal CT Plasma and 24-hr urine metanephrines and catecholamines, adrenal CT

Sleep study

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CT, computed tomography; GFR, glomerular filtration rate; MR, magnetic resonance; MRI, magnetic resonance imaging. Data from Kaplan NM: Clinical Hypertension, 8th ed. Philadelphia, Williams & Wilkins, 2002.

pelling cause is found on the initial evaluation, or (2) when the hypertensive process is so severe that it either is refractory to intensive multiple-drug therapy or requires hospitalization. Table 13-6 summarizes the major causes of secondary hypertension that should be suggested on the basis of a good history, physical examination, and routine laboratory tests.

Renal Parenchymal Hypertension Chronic kidney disease is the most common cause of secondary hypertension. Hypertension is present in more than 85% of patients with chronic kidney disease and is a major factor causing their increased cardiovascular morbidity and mortality. The mechanisms causing the hypertension include an expanded plasma volume and peripheral vasoconstriction, with the latter caused by both activation of vasoconstrictor pathways (renin-angiotensin and sympathetic nervous systems) and inhibition of vasodilator pathways (nitric oxide). Renal insufficiency should be considered when proteinuria is found by dipstick or when the serum creatinine level is greater than 1.2 mg/dL in women with hypertension or greater than 1.4 mg/dL in men with hypertension.

Renovascular Hypertension Unilateral or bilateral renal artery stenosis is present in less than 2% of patients with hypertension in a general medical practice but in up to 30% in patients with medically refractory hypertension. The main causes of renal artery stenosis are atherosclerosis (85% of patients), typically in older adults with other clinical manifestations of systemic atherosclerosis, and fibromuscular dysplasia (15% of patients), typically in women between the ages of 15 and 50 years. Unilateral renal artery stenosis leads to underperfusion of the juxta-

glomerular cells, thereby producing renin-dependent hypertension even though the contralateral kidney is able to maintain normal blood volume. In contrast, bilateral renal artery stenosis (or unilateral stenosis with a solitary kidney) constitutes a potentially reversible cause of progressive renal failure and volume-dependent hypertension. The following clinical clues increase the suggestion of renovascular hypertension: any hospitalization for urgent or emergent hypertension; recurrent flash pulmonary edema; recent worsening of longstanding, previously well-controlled hypertension; severe hypertension in a young adult or in an adult after 50 years of age; precipitously and progressively worsening of renal function in response to angiotensin-converting enzyme (ACE) inhibition or angiotensin receptor blockade (ARB); unilateral small kidney by any radiographic study; extensive peripheral arteriosclerosis; or a flank bruit. The diagnosis is confirmed by noninvasive testing with MR or spiral CT angiography (Fig. 13-11). Renal artery angioplasty often cures fibromuscular dysplasia. Atherosclerotic renal artery stenosis should be treated with intensive medical management of atherosclerotic risk factors (hypertension, lipids, smoking cessation). Revascularization should be considered for the following indications: (1) medically refractory hypertension, (2) progressive renal failure on medical therapy, and (3) bilateral renal artery stenosis or stenosis of a solitary functioning kidney.

Primary Aldosteronism The most common causes of primary aldosteronism are (1) a unilateral aldosterone-producing adenoma and (2) bilateral adrenal hyperplasia. Because aldosterone is the principal ligand for the mineralocorticoid receptor in the distal nephron, excessive aldosterone production causes excessive renal Na−-K− exchange, often resulting in hypokalemia. The

178


“String of beads” Proximal stenosis

A

B

Figure 13-11 Computed tomographic angiogram with three-dimensional reconstruction. A, Classic string-of-beads lesion of fibromuscular dysplasia. B, Severe proximal atherosclerotic stenosis of the right renal artery. (Images courtesy of Bart Domatch, MD, Radiology Department, University of Texas Southwestern Medical Center, Dallas, Texas.)

diagnosis should always be suggested when hypertension is accompanied by either unprovoked hypokalemia (serum K+ < 3.5 mmol/L in the absence of diuretic therapy) or a tendency to develop excessive hypokalemia during diuretic therapy (serum K+ < 3 mmol/L). However, more than one third of patients do not have hypokalemia on initial presentation, and the diagnosis should be considered in any patient with refractory hypertension. The diagnosis is confirmed by the demonstration of nonsuppressible hyperaldosteronism during salt loading, followed by adrenal vein sampling to distinguish between a unilateral adenoma and bilateral hyperplasia. Laparoscopic adrenalectomy is the treatment of choice for unilateral aldosterone-producing adenoma, whereas pharmacologic mineralocorticoid receptor blockade with eplerenone is the treatment for bilateral adrenal hyperplasia.

Mendelian Forms of Hypertension Nine rare forms of severe early-onset hypertension are inherited as mendelian traits. In each case, the hypertension is mineralocorticoid induced and involves excessive activation of the epithelial sodium channel (ENaC), the final common pathway for reabsorption of sodium from the distal nephron. The resultant salt-dependent hypertension can be caused by gain-of-function mutations of ENaC (Liddle syndrome) or the mineralocorticoid receptor (i.e., a rare form of pregnancy-induced hypertension) and by increased production or decreased clearance of mineralocor ticoids. These include aldosterone (glucocorticoid-remediable aldosteronism), deoxycorticosterone (17-hydroxylase deficiency), and cortisol (syndrome of apparent mineralo corticoid excess).

Pheochromocytoma Pheochromocytomas are rare catecholamine-producing tumors of the adrenal (or sometimes extra-adrenal) chromaf fin cells. The diagnosis should be suggested when hyperten-

sion is accompanied by paroxysms of headaches, palpitations, pallor, or diaphoresis. In some patients, pheochromocytoma is misdiagnosed as panic disorder. A family history of earlyonset hypertension may suggest pheochromocytoma as part of the multiple endocrine neoplasia syndromes. If the diagnosis is missed, outpouring of catecholamines from the tumor can cause an unsuspected hypertensive crisis during unrelated radiologic or surgical procedures; the perioperative mortality rate exceeds 80% in such patients. Laboratory confirmation of pheochromocytoma is made by demonstrating elevated levels of plasma or urinary metanephrines, catecholamines, or other metabolites such as vanillylmandelic acid. These are typically large tumors that can usually be localized by CT or magnetic resonance imaging (MRI), although nuclear scanning with specific isotopes that localize to chromaffin tissue is occasionally needed to identify smaller tumors. Treatment of these tumors is surgical resection. Patients must receive adequate α blockade (phentolamine), β blockade, and volume expansion before surgery to prevent the hemodynamic swings that can occur during manual manipulation of the tumor peri-operatively. For unresectable tumors, chronic therapy with the α-adrenergic blocker phenoxybenzamine is usually effective. The differential diagnosis includes other causes of neurogenic hypertension such as sympathomimetic agents (cocaine, methamphetamine), baroreflex failure, and obstructive sleep apnea. A history of surgery and radiation therapy for head-and-neck tumors suggests the possibility of baroreceptor damage. Loud snoring, obesity, and somnolence suggest obstructive sleep apnea. Weight loss, continuous positive airway pressure, and corrective surgery improve BP control in some patients with sleep apnea. Other causes of secondary hypertension include hypo thyroidism, hyperthyroidism coarctation of the aorta, and immunosuppressive drugs, especially cyclosporine and tacrolimus.


TREATMENT OF HYPERTENSION Prescription medication is the cornerstone of treating hypertension. Lifestyle modification should be used as an adjunct but not as an alternative to life-saving BP medication. Most dietary sodium comes from processed foods, and daily salt consumption can be reduced from 10 to 6 g by teaching patients to read food labels (6 g of NaCl = 2.4 g of Na+ = 100 mmol of Na+. The Dietary Approaches to Stop Hypertension (DASH) guidelines, which are rich in fresh fruits and vegetables (for high potassium content) and low-fat dairy products, has been shown to lower BP in feeding trials. Other lifestyle modifications that can lower BP include weight loss in overweight patients with hypertension, regular aerobic exercise, smoking cessation, and moderation in alcohol intake. Currently, 92 prescription medications and many fixeddose combinations are marketed for the treatment of hypertension in the United States (see Table 13-4).

WHICH DRUGS FOR WHICH PATIENTS? Patients with Uncomplicated Hypertension Choosing the best drugs to treat hypertension in a given patient comes down to two considerations: (1) effectively lowering BP and preventing hypertensive complications with minimal side effects and cost, and (2) concomitant treatment of co-morbid cardiovascular diseases (e.g., angina, heart failure). The seventh report of the U.S. Joint National Committee (JNC 7) recommends a thiazide-type diuretic as cost-effective first-line therapy for most patients with hypertension. It also recommends initiating therapy with two drugs—one being a thiazide—for stage 2 hypertension. In contrast, the European Society of Hypertension makes no specific drug class recommendation, arguing that the most effective drugs are those that the patient will tolerate and take. The British Hypertension Society advocates a treatment strategy that is based on the patient’s age and ethnicity. It recommends initiating therapy with an ACE inhibitor or ARB or a β blocker (A or B drug) for young white patients (PV

20

10

40

60

PO2

80

100

B Figure 16-9 A rising Pco2 leads to a linear increase in minute ventilation (A). The ventilatory response to hypoxemia (B) is less sensitive and is clinically relevant only when the Po2 has dropped significantly.

receptor located between the internal and external branches of carotid artery. Changes in Pao2 are sensed by the carotid sinus nerve. Neural traffic projects to the respiratory center through the glossopharyngeal nerve, which serves to modulate ventilation. The carotid body also senses changes in Paco2 and pH. Nonvolatile acids (i.e., ketoacids) stimulate ventilation through their effects on the carotid body. The outcome of this complex respiratory control system is that variables such as Pao2, Paco2, and pH are held within narrow limits under most circumstances. The respiratory control center also can adjust VT and f to minimize the energetic cost of breathing and can adapt to special circumstances such as speaking, swimming, eating, and exercise. Breathing can be stimulated when Pco2, Po2, and pH are artificially manipulated. For example, rebreathing carbon dioxide, inhaling a concentration of low oxygen, or infusion of acid into the bloodstream will increase ventilation.

PERFUSION The pulmonary vascular bed differs from the system circulation in several respects. The pulmonary vascular bed receives

the entire cardiac output of the right ventricle, whereas the cardiac output from the left ventricle is dispersed among several organ systems. Despite receiving the entire cardiac output, the pulmonary system is a low-resistance, lowpressure circuit. The normal mean systemic arterial pressure is about 100 mm Hg, whereas the normal mean pulmonary artery pressure is in the range of 15 mm Hg. The vasculature bed can passively accommodate an increase in blood flow without raising arterial pressure by recruiting more vessels in the lung. Thus, during exercise, there is little increase in pulmonary artery resistance despite a large increase in pulmonary blood flow. Hypoxic vasoconstriction also is a feature unique to the pulmonary vascular system and regulates regional blood flow. This regulation aids in matching blood flow to ventilation by reducing flow to poorly ventilated regions of the lung. In the upright individual, there is greater perfusion of the lung bases than apices (Fig. 16-10). In a low-pressure system such as the pulmonary circulation, the effects of gravity on blood flow need to be considered. Usually the arterialvenous pressure difference provides the “driving” pressure for blood flow. Although this is true for the systemic circulation, it is true only for certain regions of the lung. With the respiratory system, pulmonary blood flow also needs to be considered in the context of alveolar pressure. Venous and arterial pressures are importantly affected by gravity, whereas alveolar pressure remains constant throughout the lung, assuming the airways are open. Thus, as one descends from the apex to the base of the lung, arterial and venous pressures increase because of gravity, but alveolar pressure remains constant. At the apex of the lung, alveolar pressure may be greater than arterial pressure. This region of the lung is referred to as zone 1 and, in theory, receives no blood flow. Alveolar pressure may exceed arterial pressure under special circumstances such as hypovolemic shock, in which pulmonary arterial pressure may fall below alveolar pressure, and with very high levels of positive end-expiratory pressure

Section IV—Pulmonary and Critical Care Medicine

GAS TRANSFER Oxygen and carbon dioxide are easily dissolved in plasma. Nitrogen is much less soluble and is not significantly exchanged across the alveolar-capillary interface. The pressure gradient for oxygen between the alveolus and capillary promotes diffusion of oxygen from the alveolus to the capillary (Pao2 of 150 mm Hg versus Pao2 of 40 mm Hg). This pressure difference is greater than that driving carbon dioxide from the mixed venous blood to the alveolus (Pmvco2 of 45 mm Hg versus Paco2 of 40 mm Hg). Despite the lower driving pressure, the greater solubility of carbon dioxide allows complete equilibration between the alveolus and plasma during each respiratory cycle (Fig. 16-11). Most of the oxygen contained in the blood is bound to hemoglobin, with a small fraction dissolved and measured as the Pao2. The amount of oxygen dissolved is about 3 mL/L in arterial blood, whereas the amount of oxygen bound to hemoglobin is about 197 mL/L in arterial blood, assuming a normal hematocrit. Each molecule of hemoglobin is capable of carrying four molecules of oxygen. The shape of the oxyhemoglobin association curve reflects the cooperative binding of oxygen to hemoglobin (Fig. 16-12). In general, the percent hemoglobin saturation is between 80% and 100% with Pao2 above 60 mm Hg and drops dramatically when the Pao2 is less than 60 mm Hg. Factors that decrease the affinity of hemoglobin for oxygen include a reduction in blood pH, an increase in temperature, an increase in Pco2, and an increase in 2,3-diphosphoglyceric acid (2,3-DPG). These factors facilitate unloading of oxygen into tissues. This is seen as a shift of the oxyhemoglobin dissociation curve to the right. The oxygen carrying capacity of hemoglobin is also affected by competitive inhibitors for binding sites such as carbon monoxide. Carbon monoxide has an affinity for hemoglobin that is 240 times greater than oxygen. Thus, it will preferentially bind to hemoglobin. However, it does not affect the amount of oxygen dissolved in the blood. Someone with carbon monoxide poisoning

Pul. capillary

Pul. artery

Pul. vein

Alv PO2 = 100 mm Hg

100

PO2 (mm Hg)

(PEEP), which may increase alveolar pressure to the extent at which it becomes greater than arterial pressure. As one descends from the apex toward the midzone of the lung, arterial and venous pressures increase, and alveolar pressure remains constant. At some point, arterial pressure becomes greater than alveolar pressure. In this region, the driving pressure for blood flow is the arterial-alveolar pressure difference. This region is referred to as zone 2 of the lung. Normally, there is very little zone 2 because alveolar pressure is less than venous pressure in most of the lung. However, with high levels of PEEP, alveolar pressure will become greater than venous pressure in more lung regions. When further approaching the base of the lung, the effects of gravity on arterial and venous pressures are more pronounced, venous pressure becomes greater than alveolar pressure, and the arterial-venous pressure difference provides the driving pressure for blood flow. This region is referred to as zone 3 of the lung. Normally, most of the lung is in zone 3, and most of the perfusion is to the lung base. This inequality in perfusion from apex to base is qualitatively similar to the inequality of ventilation from apex to base, thereby optimizing the matching of ventilation and perfusion.

80 60 40 0 50

PcO2 (mm Hg)

204

45 40 0

Alv PcO2 = 40 mm Hg 0

0.25 0.50 0.75 Time (sec.) Figure 16-11 Changes in Po2 and Pco2 as blood courses from the pulmonary artery through the capillaries and into the pulmonary veins. The diffusion gradient is greater for O2 than CO2. However, equilibration of capillary and alveolar gas occurs for both molecules within the 0.75 second it takes for blood to traverse the capillaries.

may have a normal Pao2 but very low blood oxygen content due to the desaturated hemoglobin. About 5% of carbon dioxide is dissolved in plasma, and the remainder is transported in other forms. A small amount of carbon dioxide also binds to hemoglobin. However, carbon dioxide does not exhibit cooperative binding; therefore, the shape of the carbon dioxide–hemoglobin dissociation curve is linear (see Fig. 16-12). Carbon dioxide binds to the protein component of the hemoglobin molecule and to the amino groups of the polypeptide chains of plasma proteins to form carbamino compounds. About 10% of carbon dioxide is transported in this fashion. Most of the carbon dioxide is transported as bicarbonate ion. As carbon dioxide diffuses from metabolically active tissue into the blood, it reacts with water to form carbonic acid. This reaction primarily occurs in the red blood cell because it is catalyzed by the enzyme carbonic anhydrase, which resides in the red blood cell. Carbonic acid then dissociates to bicarbonate and hydrogen ion. Although there is more carbon dioxide dissolved in blood than oxygen, it is still a small fraction of the total carbon dioxide transported by blood.

ABNORMALITIES OF PULMONARY GAS EXCHANGE The Pao2 and Paco2 are determined by the degree of equilibration between the alveolar gas and capillary blood. The degree of equilibration depends on four major factors: (1) ventilation, (2) matching of ventilation with perfusion, (3) shunt, and (4) diffusion. A fifth cause of hypoxemia is a low inspired Po2. Hypoxemia refers to a reduction in the oxygen content in the blood. Specifically, hypoxemia is determined by measuring the Po2 of arterial blood. In contrast, hypoxia

Chapter 16—Evaluating Lung Structure and Function

Increased PCO2, 2,3–DPG, temp. decreased pH

12 8 4 0

20

40

60 PO2 (mm Hg)

80

100

CO2 Content (mL/dL)

A 60

Decreased PO2 Increased PO2

40

20

0

20

40 PCO2 (mm Hg)

60

B Figure 16-12 A, The oxyhemoglobin dissociation curve. The bulk of the oxygen is combined with hemoglobin. The various factors that decrease the hemoglobin oxygen affinity are shown. Opposite changes increase hemoglobin oxygen affinity, shifting the curve to the left. B, The carbon dioxide dissociation curve is more linear than the oxyhemoglobin curve throughout the physiologic range. Increased Pao2 shifts the curve to the right, which decreases carbon dioxide content for any given Paco2 and thus facilitates carbon dioxide off-loading in the lungs. The shift to the left at a lower Pao2 facilitates carbon dioxide on-loading at the tissues. DPG, diphosphoglycerate.

refers to a decrease in oxygen content of an organ, for example, myocardial hypoxemia. Hypoventilation is defined as ventilation inadequate to keep Pco2 from increasing above normal. In this situation, hypoxemia may occur when increased carbon dioxide in alveoli displaces alveolar oxygen. The reciprocal relationship between alveolar carbon dioxide and alveolar oxygen is described by the alveolar gas equation. PAO2 = [(PB − PH2 O ) × FIO2 ] − (PaCO2 R ) , where Pao2 is the partial pressure of oxygen in the alveolus; PB is barometric pressure; Ph2o is water vapor pressure; Fio2 is the fraction of inspired oxygen; and R is the respiratory exchange ratio.

(mm Hg)

16

and PCO2

Normal

From this equation, it is apparent that as alveolar ventilation falls and Paco2 rises, Pao2 will have to fall. Administering supplemental oxygen (increasing the Fio2) can reverse hypoventilation-induced hypoxemia. When breathing room air, the difference between alveolar oxygen and arterial oxygen (Pa-a gradient) is normally about 20 mm Hg. Generally, this difference increases when hypoxemia is present. However, when hypoxemia is due to hypo ventilation, the O2 gradient is within normal limits. Causes of hypoventilation are varied and range from diseases or drugs that depress the respiratory control center to disorders of the chest wall or respiratory muscles that impair respiratory pump function. Disorders associated with hypoventilation include inflammation trauma or hemorrhage in the brainstem, spinal cord pathology, anterior horn cell disease, peripheral neuropathies, myopathies, abnormalities of the chest wall such as kyphoscoliosis, and upper airway obstruction. Administering a higher Fio2 will alleviate the hypoxemia but will do little to improve the elevated Paco2. A second cause of hypoxemia is ventilation-perfusion ) mismatch. This is the most common cause of ratio ( V Q hypoxemia in disease states. In the ideal lung, ventilation and perfusion would be perfectly matched. Although both ventilation and perfusion are greater at the base relative to is lower at the base than at the apex of the lung, the V Q ranges the apex of the lung. In the normal lung, the V Q from 0.5 at the base to 3 at the apex. The overall V Q for the normal lung is 0.8. If lung disease develops, V Q is less than 0.8, the inequality may develop. If the V Q Pa-a gradient is increased, and hypoxia ensues. The Paco2 is usually within the normal range but will increase slightly at extremely low ratios (Fig. 16-13). Typically, hypoxemia seen in diseases that affect the airways, such as chronic misobstructive pulmonary disease (COPD), is due to V Q match. As with hypoxemia due to hypoventilation, admin istering a higher Fio2 improves hypoxemia due to V Q mismatch.

100 80 60 40 20

PO2

O2 Content (mL/dL)

20

205

.

Normal Moderate Severe V ˙ A/Q˙ Inequality

Normal Moderate Severe V ˙ A/Q˙ Inequality

A

B

Figure 16-13 A, The effect of increasing ventilation-perfusion ( V Q ) inequality on Pao2 and Paco2 when cardiac output and minute ventilation are held constant. B, The gas tensions change when ventilation is allowed to increase. Increased ventilation can maintain a normal Paco2 but can only partially correct the hypoxemia. (Adapted from Dantzker DR: Gas exchange abnormalities. In Montenegro H [ed]: Chronic Obstructive Pulmonary Disease. New York, Churchill Livingstone, 1984, pp 141-160.)


QS Qt = (CcO2 − CaO2 ) ( CcO2 − CvO2 ) , where QS is the shunted blood flow, Qt is the total blood flow, Cco2 is the end pulmonary capillary oxygen content; Cao2 is the arterial oxygen content; and Cvo2 is the mixed venous oxygen content. If the shunt is severe enough, patients will require mechanical ventilation and the application of positive end expiratory pressure to improve arterial oxygenation. At values less than 50% of the cardiac output, a shunt has very little effect on Paco2 (Fig. 16-14). With shunt, the Pa-a gradient is elevated, and the Paco2 is within normal range or may be low. Unlike mismatch, hypoxemia due to hypoventilation or V Q administering a high Fio2 does not improve hypoxemia due to shunt. The fourth cause of hypoxemia is diffusion impairment. With normal cardiopulmonary function, the blood spends on average 0.75 second in the pulmonary capillaries. Typically, it only takes 0.25 second for the alveolar oxygen to diffuse across the thin alveolar capillary membrane and equilibrate with pulmonary arterial blood. However, if there is impairment to diffusion across this membrane (thickening of the alveolar capillary membrane by fluid, fibrous tissue, cellular debris, or inflammatory cells), it will take longer for the oxygen in the alveoli to equilibrate with pulmonary arterial blood. If the impediment to diffusion is such that it takes longer than 0.75 second for oxygen to diffuse, hypoxemia ensues. Alternatively, if the time the red cell spends traversing the pulmonary capillary decreases to 0.25 second or less, hypoxemia may develop. Hypoxemia may only be evident during exercise in individuals with diffusion

(mm Hg)

100

80

60 and PCO2

The third cause of hypoxemia is shunt. A right-to-left shunt occurs when a portion of blood travels from the right side to the left side of the heart without the opportunity to exchange oxygen and carbon dioxide in the lung. Right to left shunts can be classified as anatomic or physiologic. With an anatomic shunt, a portion of the blood bypasses the lung by traversing through an anatomic canal. In all healthy individuals, there is a small fraction of blood in the bronchial circulation that passes to the pulmonary veins and empties into the left atrium, thereby reducing Pao2 of the systemic circulation. A smaller portion of the normal shunt is related to the coronary circulation draining through the thebesian veins into the left ventricle. Anatomic shunts found in disease states can be classified as intracardiac or intrapulmonary shunts. Intracardiac shunts occur when right atrial pressures are elevated and deoxygenated blood travels from the right atrium to the left atrium through an atrial septal defect or patent foramen ovale. Intrapulmonary anatomic shunts consist primarily of arteriovenous malformations or telangiectasias. A physiologic right-to-left shunt consists of a portion of the pulmonary arterial blood passing through normal vasculature but not coming into contact with alveolar air. This is an extreme example of ventilation-perfusion = 0). Physiologic shunt can be due to mismatch ( V Q diffuse flooding of the alveoli with fluid, as seen with congestive heart failure or acute respiratory distress syndrome. Alveolar flooding with inflammatory exudates as seen in lobar pneumonia also causes a shunt. The fraction of blood shunted can be calculated when the Fio2 is 100% by using the following equation.

PO2

206

40

20

0

10

20

30

40

50

Percent shunt Figure 16-14 The effect of increasing shunt on the arterial Pao2 and Paco2. The minute ventilation has been held constant in this example. Under usual circumstances, the hypoxemia would lead to increased minute ventilation and a fall in the Paco2 as the shunt increases. (From Dantzker DR: Gas exchange abnormalities. In Montenegro H [ed]: Chronic Obstructive Pulmonary Disease. New York, Churchill Livingstone, 1984, pp 141-160.)

impairment because of the shortened red cell transit time. In this instance, the O2 gradient may be normal at rest but increases with exercise. With diffusion impairment, the Paco2 generally is within the normal range. As with hypox mismatch, adminisemia due to hypoventilation and V Q tering a higher Fio2 improves hypoxemia due to impaired diffusion. A fifth cause of hypoxemia is due to low inspired oxygen. This is seen at an altitude at which the fraction of inspired oxygen is normal, but the partial pressure of oxygen is low because barometric pressure is low (Patm). Rarely, circumstances occur in which the Fio2 is low (e.g., rebreathing air). Hypoxemia due to low inspired oxygen is associated with a normal O2 gradient and is usually accompanied by a low Paco2. Providing supplemental oxygen will correct this form of hypoxemia. Finally, a low mixed venous Po2 will predispose individuals to hypoxia (Fig. 16-15).

Evaluation of Lung Function Pulmonary function tests evaluate one or more major aspects of the respiratory systems. Accurate measurements of lung volumes, airway function, and gas exchange require a pulmonary function testing laboratory. Pulmonary function tests are commonly used to aid in the diagnosis of disease and assess disease severity. In addition, they are helpful in monitoring the course of the disease, assessing risk for surgical procedures, and measuring the effects of varied environmental exposures. Assessment of bronchodilator response or other forms of treatment also can be evaluated with serial pulmonary function tests (Table 16-1). Accurate interpretation of pulmonary function tests requires the appropriate reference standards. Variables that affect the predicted

Chapter 16—Evaluating Lung Structure and Function Inspiratory reserve volume

Arterial oxygen content (mL/dL)

22 Normal lung

21 20

.

Total lung capacity

40% Shunt

Expiratory reserve volume Functional residual capacity Residual volume

18 17 16 15

20

30 40 Mixed venous PO2 (mm Hg)

Vital capacity

Tidal volume

.

Va/Q Inequality

19

207

50

Figure 16-15 The effect of altering mixed venous PVo2 on the arterial oxygen content under three assumed conditions: a ) inequality, and normal lung, severe ventilation-perfusion ( V Q the presence of a 40% shunt. For each situation, the patient is breathing 50% oxygen and the PVo2 or mixed venous Po2 is altered, keeping all other variables constant. (From Dantzker DR: Gas exchange in the adult respiratory distress syndrome. Clin Chest Med 3:57-67, 1982.)

Figure 16-16 Lung volumes and capacities. Although spirometry can measure vital capacity and its subdivisions, calculation of residual volume requires measurement of functional residual capacity by body plethysmography, helium dilution technique, or nitrogen washout.

Table 16-1 Indications for Pulmonary Function Testing

standards for pulmonary function tests include age, height, gender, race, and hemoglobin concentration. Spirometry is the simplest means of measuring lung function and can be performed in an office practice. A spirometer is an apparatus that measures inspiratory and expiratory volumes. Flow rates can be calculated from tracings of volume versus time. Typically, vital capacity (VC) is measured as the difference between a full inspiration to total lung capacity (TLC) and a full exhalation to residual volume (RV) (Fig. 16-16). Flow rates are measured after instructing someone to forcefully exhale from TLC to RV. Such a forced expiratory maneuver allows one to calculate the forced expired volume in 1 second (FEV1) and the forced vital capacity (FVC) (Fig. 16-17). A value of 80% to 120% predicted is considered normal for FVC. Normally, people can exhale more than 75% to 80% of their FVC in the first second, and the majority of FVC can be exhaled in 3 seconds. The ratio of these two variables is normally more than 0.8.

Volume

FEV1

FVC

MMEF or FEF25–75 0

1

2 Time (sec) Normal

3

FVC

FEV1 Volume

• Evaluation of signs and symptoms • Shortness of breath, exertional dyspnea, chronic cough • Screening at-risk populations • Monitoring pulmonary drug toxicity • Follow-up abnormal study • Chest radiograph, electrocardiogram, arterial blood gases, hemoglobin • Preoperative assessment • Assess severity • Follow response to therapy • Determine further treatment goals • Assess disability

MMEF or FEF25–75 0

1

2 3 4 5 Time (sec) Obstructed Figure 16-17 Spirometry in a normal individual and in a patient with obstructive lung disease. FEV1 represents the forced expired volume in 1 second, and FVC represents the forced vital capacity. The slope of the line connecting the points at 25% and 75% of the FVC represents the forced expired flow (FEF at 25% to 75%) or maximum mid-expiratory flow (MMEF). The FEF at 25% to 75% is less reproducible and less specific than the FEV1.

208


Spirometry can reveal abnormalities that are classified into two patterns—obstructive and restrictive. Obstructive impairments are defined by a low FEV1/FVC ratio. Diseases characterized by an obstructive pattern include asthma, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, and some central airway lesions. The reduction in FEV1 (expressed as % predicted FEV1) is used to determine the severity of airflow obstruction (Web Fig. 16-2). Peak expiratory flow rate (PEFR) can be measured as the maximal expired flow rate obtained during spirometry or when using a hand-held peak flow meter. The lower the peak expiratory flow rate, the more significant the obstruction. The peak flow meter can be used at home or in the emergency department and to evaluate the presence of obstruction. Severe attacks of asthma, for example, are usually associated with peak expiratory flow rates of less than 200 L per minute (normal is 500 to 600 L per minute). A restrictive pattern is characterized by loss of lung volume. With spirometry, both the FVC and FEV1 are reduced with a normal FEV1/FVC ratio. The restrictive pattern must be confirmed by measurements of lung volumes. Lung volumes are measured using body plethysmography or by dilution of an inert gas such as helium. Lung volumes that can be measured with these techniques include FRC, TLC, and RV (see Fig. 16-16). As mentioned previously, FRC is the lung volume at which the inward elastic recoil of the lung equals the outward elastic recoil of the chest wall. Changes in FRC reflect abnormalities in lung elastic recoil. Diseases associated with increased elastic recoil such as pulmonary fibrosis are associated with a reduction in FRC, whereas those with decreased recoil such as emphysema are associated with an increase in FRC. TLC is the amount of air in the thorax after a maximal inspiration and is determined by the balance of the forces generated by the respiratory muscles to expand the respiratory system and the elastic

PEF

recoil of the respiratory system. Restrictive lung disease is defined as a TLC less than 80% predicted, whereas values of TLC greater than 120% predicted are consistent with hyperinflation. The lower the percent predicted TLC, the more severe the restrictive impairment. Restriction may be due to disorders of the lung, chest wall, respiratory muscles, or pleural space. Lung diseases that cause pulmonary fibrosis will cause a restrictive pattern because of the increased elastic recoil of the respiratory system. Diseases of the chest wall, such as kyphoscoliosis, obesity, and ankylosing spondylitis can also cause restriction by reducing the elasticity of the chest wall. Weakness of the respiratory muscles causes restriction by reducing the force available to inflate the respiratory system. Myasthenia gravis, amyotrophic lateral sclerosis, diaphragm paralysis, and Guillain-Barré syndrome can be associated with weakness sufficient to cause restrictive lung disease. Finally, space-occupying lesions involving the pleural space such as pleural effusions, pneumothorax, or pleural tumors can cause restriction. Occasionally, RV and FRC may be elevated with no increase in total lung capacity. This pattern is referred to air trapping and can be seen with COPD or asthma. The forced expiratory maneuver can be analyzed in terms of flow and volume, that is, a flow-volume loop (Fig. 16-18). Flow-volume loops are useful when identifying obstructive and restrictive patterns. The characteristic appearance of obstructive impairment is concavity (“scooping”) of the expiratory loop (Web Fig. 16-3). With restrictive impairments, the loops are similar in appearance to normal but reduced in size. In addition, flow-volume loops are the primary means of identifying upper airway obstruction. Upper airway obstruction is characterized by a truncated (clipped) inspiratory or expiratory loop. A fixed obstruction has clipping of both inspiratory and expiratory loops. Variable intrathoracic upper airway obstruction exhibits

Expiration

Normal UAO

OLD

FEF75

PIF

RLD

Flow

Flow

FEF50

Inspiration Volume

A

Volume

B

Figure 16-18 A, The maximum expired flow and volume curve in a normal individual. The peak expiratory flow (PEF) and forced expiratory flows at 50% and 75% of the exhaled vital capacity (FEF at 50% and 75%) are indicated. PIF, peak inspiratory flow. B, In obstructive lung disease (OLD), hyperinflation pushes the position of the curve to the left, and characteristic scalloping on expiration develops. In restrictive lung disease (RLD), lung volumes are reduced, but flow for any point in volume is normal. The flow-volume curve displays different patterns with various forms of upper airway obstruction (UAO), with reduction in respiratory flow if the obstruction is outside the thoracic cavity and, in addition, in expiratory flow if the obstruction is caused by a fixed deformity.

Chapter 16—Evaluating Lung Structure and Function clipping of the expiratory loop, whereas variable extrathoracic obstruction exhibits clipping of the inspiratory loop (see Fig. 16-18).

BRONCHOPROVOCATION TESTING Bronchoprovocation testing is typically used to determine the presence or absence of hyperreactive airways disease. Some individuals in whom there is a clinical suspicion of asthma may have normal expiratory flow rates and lung volumes. Bronchoprovocation testing in these individuals can be important in identifying hyperreactive airways disease and supporting the diagnosis of asthma. Methacholine is a cholinergic agonist that causes bronchoconstriction. Individuals with hyperreactive airways exhibit airflow limitation after inhaling low concentrations of methacholine. During the bronchoprovocation test, the subject inhales increasing concentrations of methacholine. Measurements of FEV1 and FVC, as well as specific airways conductance, are obtained after the inhalation of each concentration. If the FEV1 is reduced by 20% or more or the specific airways conductance is reduced by 40% or more, a diagnosis of hyperreactive airways disease can be ascertained. Patients with asthma demonstrate a fall in FEV1 of 20% from baseline at doses considerably smaller than normal individuals (Fig. 16-19).

LUNG DIFFUSION CAPACITY The diffusion of oxygen from the alveolus into the capillary can be assessed by measuring the diffusion capacity for carbon monoxide. To calculate diffusion capacity for oxygen, one needs to know the alveolar volume and the partial pressure of oxygen in the alveolus and in the pulmonary capil-

120

FEV1 (% control)

100

80

60

PC20 = 3.0 PC20 = 25

Baseline Saline 0.1 1.0 10.0 100 Methacholine/histamine concentration (mg/mL) Figure 16-19 Bronchoprovocation challenge. Patients are exposed to increasing concentrations of an inhaled challenge (e.g., methacholine, histamine) followed by evaluation of FEV1 (percent control, PC). The FEV1 falls at lower concentrations of the challenge drug in a patient with asthma (blue circles) when compared with an individual without asthma (red circles).

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lary. Because it is not practical to measure the oxygen tension of pulmonary capillary blood, carbon monoxide is used rather than oxygen to assess diffusion capacity. Carbon monoxide diffuses across the alveolar capillary membranes much as oxygen does. However, carbon monoxide has the advantage of completely binding to hemoglobin. Therefore, the partial pressure of carbon monoxide in the pulmonary venous blood is negligible. Diffusion capacity for carbon monoxide (Dlco) is then measured as the rate of disappearance of carbon monoxide from the alveolus and is used as a surrogate for oxygen diffusion capacity. This measurement provides an overall assessment of gas exchange and depends on factors including the surface area of the lung, the physical properties of the gas, perfusion of ventilated areas, hemoglobin concentration, and the thickness of the alveolar-capillary membrane. Thus, an abnormal Dlco may not only signify disruption of the alveolar-capillary membrane but may also be related to a reduction in surface area of the lung (pneumonectomy), poor perfusion (pulmonary embolus), or poor ventilation of alveolar units. An increased Dlco may be associated with engorgement of the pulmonary circulation with red blood cells or polycythemia. A low Dlco may be seen in interstitial lung diseases that alter the alveolar-capillary membrane or diseases such as emphysema that destroy both alveolar septa and capillaries (Web Fig. 16-4). Anemia lowers the Dlco. Most laboratories provide a hemoglobin correction for diffusion capacity.

ARTERIAL BLOOD GASES The measurement of Pao2 and Paco2 provides information about the adequacy of oxygenation and ventilation. This requires arterial blood sampling through arterial puncture or indwelling cannula (Table 16-2). Oxygenation can also be measured through noninvasive devices including the pulse oximeter, which measures hemoglobin oxygen saturation, and through transcutaneous devices that measure Pao2 and Paco2. These devices are particularly useful for measuring oxygenation during exertion in the office setting. Often, alterations in oxygenation are not detected at rest, but they are unveiled during exertion. The 6-minute walk test is a standardized test in which the patient walks for 6 minutes while the oxygen hemoglobin saturation is measured. A decrease in the oxygen hemoglobin saturation is abnormal and suggests impaired gas exchange capabilities. In summary, pulmonary function tests, in conjunction with history and physical examination, can be used to diagnose pulmonary disorders and assess severity and response to therapy, as illustrated in the flow diagram (Web Fig. 16-5).

Table 16-2 Normal Values for Arterial Blood Gases Po2: 104 − (0.27 × age) Pco2: 36-44 pH: 7.35-7.45 Alveolar-arterial O2 difference = 2.5 + 0.21 × age

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Evaluation of Lung Structure CHEST RADIOGRAPH Generally, the evaluation of a patient with lung disease begins with routine chest radiography and then proceeds to more specialized techniques such as computed tomography (CT) or magnetic resonance imaging (MRI). Ideally, the chest radiograph consists of two different films, a postero anterior (PA) radiograph and a lateral radiograph (Web Fig. 16-6). Many pathologic processes can be identified on a PA chest radiograph; however, the lateral view adds valuable information about areas that are not well seen on the PA projection. In particular, the retrocardiac region, the posterior bases of the lung, and the bony structure of the thorax such as the vertebral column are visualized better on the lateral radiograph. The PA chest radiograph is obtained with the patient standing with his or her back to the x-ray beam and the anterior chest wall placed against the film cassette. The chest radiograph should be obtained while the patient takes the deepest breath possible. When the patient is too weak to stand or too sick to travel to the radiology department, the cassette is placed behind the patient’s back, and the x-ray beam travels from anterior to posterior (AP film). The quality of a portable film is not that of a standard PA film, but it still provides valuable information. The approach to examining a chest radiograph should be systematic so that subtle abnormalities are not missed. An examination of a chest radiograph includes evaluating the lungs and pulmonary vasculature, the bony thorax, the heart and great vessels, the diaphragm and pleura, the mediastinum, the soft tissues, and the subdiaphragmatic areas. Abnormalities seen on a chest radiograph include pulmonary infiltrates, nodules, interstitial disease, vascular disease, masses, pleural effusions and thickening, cavitary lung disease, cardiac enlargement, some airway diseases, and vertebral or rib fractures. In addition to the PA and lateral chest radiographs, the lateral decubitus projection is often used to identify the presence or absence of pleural effusion. The decubitus view is particularly useful in determining whether blunting of the costal phrenic sulcus is due to freely flowing pleural fluid or related to pleural thickening. The chest radiograph in concert with a good history and physical examination allows the clinician to diagnose chest disease in many circumstances.

FLUOROSCOPY Fluoroscopic examination of the chest is useful in evaluating motion of the diaphragm. This technique is particularly helpful in diagnosing unilateral diaphragm paralysis. A paralyzed hemidiaphragm moves paradoxically when the patient is instructed to inhale or forcefully sniff. However, fluoroscopy is limited when evaluating for bilateral diaphragm paralysis. Because of compensatory respiratory strategies in the setting of bilateral diaphragm paralysis, apparent normal descent of the diaphragm may be seen during inspiration, leading to a false-negative result by fluoroscopy. Furthermore, paradoxical hemidiaphragm motion is seen in as many as 6% of normal subjects during the sniff maneuver. This observation leads to a false-positive interpretation.

Alternatively, two-dimensional B-mode ultrasound of the diaphragm can be used to visualize diaphragm contraction during inspiration. With this technique, the diaphragm muscle is visualized in the zone of apposition of the diaphragm to the rib cage. Absence of contraction correlates with the absence of active transdiaphragmatic pressure and indicates diaphragm paralysis. This technique can be used to diagnose bilateral and unilateral diaphragm paralysis.

COMPUTED TOMOGRAPHY CT has many applications in pulmonary medicine and provides more detailed information about lung structure than chest radiography. Using this technique, cross sections of the entire thorax can be obtained, usually at 1-cm intervals. Image contrast can be adjusted to optimize visualization of the lung parenchyma or pleural and mediastinal structures. The use of intravenous contrast material as part of the examination permits separation of vascular from nonvascular mediastinal structures. CT of the chest adds tremendous anatomic detail when compared with chest radiography. Its increased resolution permits elucidation of many findings. It helps to characterize pulmonary nodules and masses, distinguish between pleural thickening and pleural fluid, estimate the size of the heart and presence of pericardial fluid, identify patterns of involvement of interstitial lung disease, detect cavities, identify intracavitary processes such as mycetomas, quantify the extent and distribution of emphysema, detect and measure mediastinal adenopathy for staging of lung cancer, and identify vascular invasion by neoplasm. Newer generations of CT scanners are able to use multiple x-ray beams so that 4 to 64 images are created simultaneously at a much faster rate than the older models, which used only a single x-ray beam and detector. CT angiography allows for construction of threedimensional images of the pulmonary vascular system. This imaging technique has emerged as the procedure of choice for identifying pulmonary embolism supplanting pulmonary ventilation-perfusion scintigraphic lung scanning. The technique also can be used to identify pulmonary vascular abnormalities such as aortic dissection, pulmonary venous malformations, and aortic aneurism. High-resolution CT is a technique that generates thin anatomic slices (1 mm) to provide a high-contrast image of the pulmonary parenchyma. With high-resolution CT, a special reconstruction algorithm sharpens the soft tissue interfaces to provide superior visualization of the pulmonary parenchyma. This technique primarily is used to identify inter stitial lung disease and bronchiectasis. It is extremely useful in identifying interstitial lung disease that may not be apparent on a plain chest radiograph and has supplanted bronchography in the diagnosis of bronchiectasis.

MAGNETIC RESONANCE IMAGING MRI is a tomographic technique that uses radio waves modified by a strong magnetic field to produce an image. It provides images that are similar to those produced with CT but with better definition of vascular structures. MRIs can be constructed in one of several anatomic planes. Although the standard image is usually an axial view, sagittal and coronal images can be easily created from the information obtained

Chapter 16—Evaluating Lung Structure and Function at the time of the study. Intravenous administration of gadolinium acts as a contrast agent and allows better visualization of vascular structures. MRI can be used to study aortic dissection and may have a role in the evaluation of pulmonary emboli.

PULMONARY ANGIOGRAPHY Pulmonary angiography entails placement of a catheter in the pulmonary artery followed by rapid injection of contrast. Angiography was the gold-standard for diagnosing pulmonary thromboembolic disease. Pulmonary angiography can be useful in detecting congenital abnormalities of the pulmonary vascular tree, but CT and MRI have largely supplanted pulmonary angiography.

POSITRON-EMISSION TOMOGRAPHY Positron-emission tomography (PET) detects metabolically active masses greater than 1 cm in diameter. It is helpful in assessing whether a pulmonary nodule is benign or malignant. However, it does not distinguish between inflam mation and malignancy. Thus, assessment of multiple pulmonary nodules using PET scanning is limited because of false-positive findings due to active granulomatous disease such as tuberculosis, sarcoidosis, or fungal infections. Dualmodality integrated PET-CT combines morphologic and functional imaging. The combination of PET and CT is helpful in localizing solitary metastatic lymph nodes in the hilum, which allows better staging of lung cancer. In addition, PET-CT is helpful in planning radiation therapy for patients with lung cancer associated with atelectasis.

BRONCHOSCOPY Fiberoptic bronchoscopy is used for diagnostic or therapeutic indications. It is most commonly performed to directly visualize the nasopharynx, larynx, vocal cords, and proximal tracheobronchial tree for diagnostic purposes. The procedure is performed by sedating the patient and providing

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local anesthesia with inhaled and bronchoscopically instilled lidocaine. The bronchial mucosa is assessed for endobronchial masses, mucosal integrity, extrinsic compression, dynamic compression, and hemorrhage. The bronchoscope is equipped with a channel for passage of biopsy forceps, bronchial brushes, or needles for aspiration and tissue biopsy. Saline also can be instilled through the channel for bronchial washings or bronchoalveolar lavage. Bronchial washings can be analyzed for cytology, culture, and special stains. A bronchial brush is used to scrape the bronchial mucosa and harvest cells for cytology. Bronchoscopes can also be adapted to provide ultrasound images of the airways and neighboring tissues. Endobronchial ultrasound (EBUS) uses high acoustic frequencies, in the range of 20 MHz, which provide high-resolution images of proximal tissue. EBUS can provide guidance for needle aspiration of mediastinal lymph nodes. Common therapeutic indications for bronchoscopy include the retrieval of foreign bodies, suctioning of secretions, re-expansion of atelectatic lung, and assistance with difficult endotracheal intubations. In special centers, bronchoscopy is used to perform YAG laser therapy of endobronchial lesions, guide placements of catheters for brachytherapy of lung cancer, or guide placement of stents. Lasers produce a beam of light that can induce tissue vaporization, coagulation, and necrosis. Cryotherapy probes induce tissue necrosis through hypothermic cellular crystallization and microthrombosis. Cryotherapy and electrocautery have been used to treat and relieve airway obstruction caused by benign tracheal bronchial tumors, polyps, and granulation tissue. The goal of endobronchial brachytherapy is to relieve airway obstruction from central tumors. This is generally used as an adjunct to conventional external-beam irradiation. Tracheobronchial stenting can be performed to manage airway compression associated with malignant tumors, tracheoesophageal fistulas, and tracheobronchomalacia. Bronchoscopy is generally a safe procedure, with major complications, including significant bleeding, pneumo thorax, and respiratory failure, occurring in 0.1% to 1.7% of patients.

Prospectus for the Future Continued refinement and evolution of techniques and methods currently used to assess pulmonary structure and function will enhance our ability to diagnose and treat individuals with lung disease. Although pulmonary function testing has been performed for decades, advances in equipment design and better standardization of methods will improve accuracy and reproducibility. Further development of noninvasive techniques used to measure changes in lung volume from body surface displacements may allow for assessment of pulmonary function in settings outside of the pulmonary function laboratory. Great strides in assessing lung structure will evolve from advances in CT, PET, and MRI technology. CT volume-rendering techniques will provide images of the central airways enabling “virtual bronchoscopy.” This technique may be useful to guide biopsy location for conventional bronchoscopy and allow visualization of airways distal to an endobronchial obstruction. Volumetric measurements of pulmonary nodules using CT seg-

mentation techniques will allow more accurate calculation of nodule volume and better assessment of tumor doubling times. This, in concert with PET-CT, may provide more accurate means of determining malignant potential of solitary pulmonary nodules. MRI may evolve into the preferred method for evaluating pulmonary emboli and mediastinal disease. Velocityencoded MRI is a promising modality for assessing pulmonary vascular blood flow and pressures, which may prove to be more accurate than current noninvasive methods. Lymph node specific magnetic resonance contrast agents and the development of PET molecular tracers targeting tumor proteins and receptors may better differentiate enlarged lymph nodes due to hyperplasia from those due to neoplasia. Finally, new insights into function of the respiratory control centers in the cortex and brainstem may be attained from studies using functional MRI of the brain.

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References McCool FD, Hoppin FG Jr: Respiratory mechanics. In Baum GL (Ed-in-Chief): Textbook of Pulmonary Diseases. Philadelphia, Lippincott-Raven Publishers, 1998, pp 117-130. Miller WT: Radiographic evaluation of the chest. In Fishman AP (Ed-in-Chief): Fishman’s Pulmonary Diseases and Disorders. New York, McGraw-Hill, 2007, pp 455-510.

Wagner PD: Ventilation, pulmonary blood flow, and ventilation-perfusion relationships. In Fishman AP (Ed-in-Chief): Fishman’s Pulmonary Diseases and Disorders. New York, McGraw-Hill, 2007, pp 147-160. West JB: Respiratory Physiology: The Essentials, 5th ed. Baltimore, Williams & Wilkins, 1995. West JB, Wagner PD: Pulmonary gas exchange. Am J Respir Crit Care Med 157:S82-S87, 1988.

Chapter

17

IV

Obstructive Lung Diseases Matthew D. Jankowich

T

he obstructive lung diseases are a group of common pulmonary disorders resulting in dyspnea charac terized by an obstructive pattern of expiratory airflow limitation on spirometry. These disorders include chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, bronchiectasis, and the bronchiolar disorders. COPD is a clinical term encompassing varied pathophysiologic processes, including emphysema, chronic bronchitis, and small airways disease, one or more of which may be prominent in a given patient with this disorder. COPD is characterized in general by abnormal airway inflammation and abnormal lung structure in response to an inhaled irritant, typically cigarette smoke, resulting in irreversible or incompletely reversible airflow limitation. Asthma is distinguished from COPD by characteristic bronchial smooth muscle hyperreactivity and reversible airflow limitation and by its frequent association with atopy (Fig. 17-1). These disorders are epidemic in the general population and account for a significant proportion of the morbidity and mortality associated with the obstructive lung diseases. All the obstructive lung disorders cause an obstructive pattern of expiratory airflow limitation, although the basis for airflow obstruction varies among disorders. The flow of air through the bronchial tree is directly proportional to the driving pressure and is inversely proportional to the resistance. In obstructive lung disease, alterations in one or both of these processes might be present. For example, in emphysema, airflow limitation is caused by decreased elastic recoil resulting in decreased driving pressure. By contrast, in asthma, airflow limitation is due to bronchoconstriction that increases airway resistance. Airway obstruction to flow causes characteristic changes in lung volumes. The residual volume and functional residual capacity are increased, whereas the total lung capacity remains normal or is increased. Vital capacity is reduced by the increase in residual volume. Several factors may contribute to the increase in functional residual capacity and residual volume in obstructive lung disease. Decreased lung elastic recoil in emphysema increases the functional residual capacity because of reduced opposition to the outward force exerted by the chest wall. Loss of airway tone and decreased tethering by surrounding lung in COPD, as well as bronchoconstriction and mucus plugging in acute asthma, allow airways to collapse at higher

lung volumes and trap excessive air. Finally, under demands for increased minute ventilation such as during exercise, the increased resistance to airflow may not allow the lungs to empty completely during the time available for expiration, leading to so-called dynamic hyperinflation of the lungs as the volume of trapped air progressively increases while the inspiratory capacity is progressively limited. The three major consequences of the changes in lung volume seen with obstructive lung disease are as follows: (1) Breathing at higher lung volumes requires a higher change in pressure for the same change in lung volume, and this requirement increases the work of breathing. (2) Larger lung volumes place the inspiratory muscles at a mechanical disadvantage. The diaphragm is flattened, thereby decreasing its ability to change intrathoracic volume, and all the inspiratory muscle fibers are shortened, decreasing the tension they are able to exert to effect changes in lung volume. (3) Lung volumes are larger, resulting in tethering of the narrowed and collapsing airways by the surrounding lung parenchyma, tending to retain airway patency and reduce airway resistance and air trapping; this consequence is beneficial. These three physiologic derangements explain many of the clinical features of obstructive lung diseases (Table 17-1). Although the consequences to lung function are relatively similar in the obstructive lung diseases, their pathogenesis, treatment, and prognosis are different. Therefore, a careful evaluation is needed to reach a definitive diagnosis that will guide targeted therapy.

Chronic Obstructive Pulmonary Disease COPD results in slowly progressive dyspnea and is characterized by abnormalities of airway and lung structure occurring in response to noxious inhaled substances, especially cigarette smoke. The abnormalities of airway and lung structure in COPD result in irreversible airflow limitation, the physiologic hallmark of COPD. The term COPD encompasses emphysema, chronic bronchitis, and small airways disease, pulmonary disorders that have common clinical 213

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manifestations and often co-exist in the same patient. The term excludes other causes of airflow obstruction, such as asthma, although in practice these diseases may at times overlap. COPD is one of the most common disorders seen by physicians, and it is the fourth leading cause of death in the United States. There are an estimated 1,500,000 emergency department visits related to COPD annually, and about 700,000 patients with COPD are hospitalized each year. From 1997 to 2001, about 90,000 deaths per year attributable to COPD occurred in the United States. Although COPD has historically been more prevalent in males than females, the prevalence of COPD in females has been increasing, and annual death rates for COPD have been steadily rising in

Chronic bronchitis

Emphysema Other disorders with airflow obstruction Chronic bronchiolitis

COPD

ABPA Other causes Asthma Cystic fibrosis Bronchiectasis Figure 17-1 Classification of obstructive lung diseases. COPD, chronic obstructive lung disease.

both white and black women. Prevalence rates for COPD are correlated with increasing age, lower socioeconomic status, and smoking. Cigarette smoking is by far the most common cause of COPD; however, other factors such as inhalation of cooking fire smoke, air pollution, occupational exposures to dust and fumes, and infections contribute to the occurrence, severity, and progression of the disease. Although cigarette smoking is the most common cause, it is important to note that only 20% of smokers are thought to develop clinically significant COPD (although many more may experience some loss of lung function). This finding suggests that COPD results from a susceptibility to environmental factors (e.g., tobacco) as a result of a genetic predisposition. A genetic predisposition is also implied by the documentation of familial clusters of COPD. Several longitudinal studies have defined patterns of age-related decline in lung function and have documented the concept of susceptibility to COPD. These studies show that most adult nonsmoking men exhibit a decline in forced expiratory volume in 1 second (FEV1) of 35 to 40 mL per year. This rate is increased to 45 to 60 mL per year in most cigarette smokers. However, the susceptible smoker may demonstrate losses of 70 to 120 mL per year (Fig. 17-2). This information allows the physician to project the rate of decrease of lung function in patients with COPD and assess the effects of therapeutic interventions. Although COPD results in chronic, progressive dyspnea, periodic acute exacerbations are characteristic of COPD. Exacerbations are characterized by a rapidly developing worsening of pulmonary function respiratory symptoms such as cough and sputum production. Acute exacerbations are associated with various triggers, including viral or bacterial respiratory infections, air pollution, and cardiac failure. Exacerbations vary widely in severity, but severe exacerbations may lead to hospitalization, acute respiratory failure, and death. Following an exacerbation, a patient may take weeks to return to a baseline level of function. Patients with

Table 17-1 Features of Obstructive Lung Diseases Disorder

Clinical Features

Laboratory Findings

Chronic obstructive pulmonary disease Emphysema

Chronic progressive dyspnea

Decreased expiratory flow rates, hypoxia and hypercapnia in end-stage disease Hyperinflation, increased compliance, low DLco, rarely α1-antitrypsin deficiency Nonspecific; rarely occurs in isolation without varying degrees of emphysema Airway hyperreactivity, response to bronchodilators

Chronic bronchitis Asthma Bronchiectasis Immotile cilia syndrome Hypogammaglobulinemia Cystic fibrosis

Little or no sputum, end-stage cachexia Sputum, history of smoking, industrial exposure Episodic dyspnea, cough, wheezing, with or without environmental triggers Usually large volume of sputum Situs inversus, dextrocardia, sinusitis, infertility Sinusitis, bronchiectasis, meconium ileus, malabsorption, infertility

Chest radiograph: dilated bronchi, thick-walled, tram track shadows, obstruction with or without restriction on pulmonary function tests Abnormal dynein in ciliated cells Decrease in one or more immunoglobulins Increased sweat chloride, mutation in CFTR chloride channel, elevated fecal fat, abnormal nasal mucosal potential difference

CFTR, cystic fibrosis transmembrane conductance regulator; DLco, diffusion capacity for carbon monoxide.

Chapter 17—Obstructive Lung Diseases FEV1 (% of value at age 25)

100

Never smoked or not susceptible to smoke

75 50

Smoked regularly and susceptible to its effects

Stopped at 45

Disability 25

Stopped at 65

Death 0

75 Age (yr) Figure 17-2 Pattern of decline in forced expiratory volume in 1 second (FEV1) with risks for morbidity and mortality from respiration disease in a susceptible smoker in comparison with a normal patient and with a nonsusceptible smoker. Although cessation of smoking does not replenish the lung function already lost in a susceptible smoker, it decreases the rate of further decline. (Data from Fletcher C, Peto R: The natural history of chronic airflow obstruction. BMJ 1:1645-1648, 1977.) 25

50

frequent exacerbations of COPD appear to experience an accelerated rate of decline in FEV1. The only genetic disorder thus far definitively linked to COPD is α1-antitrypsin deficiency, which accounts for less than 1% of all cases. The deficient enzyme, α1-antitrypsin, an acute-phase reactant, is produced primarily in the liver, from which it travels to the lung, where it deactivates elastases released by inflammatory cells that are capable of degrading connective tissue matrices. In doing so, α1-antitrypsin prevents the uncontrolled degradation of elastin in the lung parenchyma and protects against the development of emphysema. Individuals with the ZZ genotype of α1antitrypsin deficiency produce mutant forms of α1antitrypsin that have a tendency to inappropriately polymerize within the hepatocyte, leading to a deficiency in secreted α1-antitrypsin and in some cases to collateral damage to the liver caused by accumulation of intracellular misfolded, mutant α1-antitrypsin. Patients who develop emphysema at a young age (400 mg/day Acute Weeks or months Subacute or chronic

Pneumonitis, fibrosis

Acute

Pulmonary edema, bronchospasm

Opiates Cocaine

Acute Acute

Talc (in intravenous and inhaled illicit drugs)

Acute or chronic

Pulmonary edema Pulmonary edema, diffuse alveolar damage, pulmonary hemorrhage, BOOP Granulomatous interstitial fibrosis, granulomatous pulmonary artery occlusion, particulate embolization

Chemotherapeutic Bevacizumab Bleomycin

Antimicrobial Nitrofurantoin Sulfasalazine Cardiovascular Amiodarone Flecainide Tocainide Procainamide

ARDS, LIP Pneumonitis Drug-induced systemic lupus erythematosus, pleural effusions, pulmonary infiltrates

Anti-inflammatory Aspirin Illicit

Tocolytics Terbutaline, albuterol, ritodrine

Acute

Pulmonary edema

ARDS, acute respiratory distress syndrome; BOOP, bronchiolitis obliterans and organizing pneumonia; LIP, lymphoid interstitial pneumonia.

high levels of inspired oxygen may precipitate bleomycin lung injury and should be avoided if possible in exposed patients. The website http://www.pneumotox.com is an online reference site tabulating the reported pulmonary toxicities of various drugs that is searchable by drug name as well as by pattern of lung involvement.

Pulmonary Vasculitis and Diffuse Alveolar Hemorrhage Diffuse alveolar hemorrhage (DAH) syndromes encompass diverse group of specific entities that are all characterized by the disruption of the alveolar-capillary membrane, resulting in bleeding into the alveolar spaces. Unfortunately, patients with DAH do not always present with signs, symptoms, and

laboratory and radiographic findings that support a specific underlying diagnosis. Often, DAH is found without features that identify a specific etiology. All DAH syndromes are characterized by the abrupt onset of cough, fever, and dyspnea. Hemoptysis is common but not universal because it may be absent in up to one third of patients with DAH. Physical findings are generally nonspecific, although ocular, nasopharyngeal, or cutaneous abnormalities may suggest systemic vasculitis or collagen vascular disease as an etiology. The cardiopulmonary examination is often normal but may reveal inspiratory crackles, a systolic murmur suggestive of mitral stenosis or evidence of pulmonary hypertension. Falling hemoglobin levels, the presence of increasingly hemorrhagic fluid on sequential bronchoalveolar lavage and new patchy alveolar infiltrates (Web Fig 18-6) by chest imaging favor the diagnosis of DAH. Other laboratory abnormalities may include the presence of azotemia, suggesting a pulmonary-renal syndrome. In this setting, an abnormal urinalysis with proteinuria, hematuria, and red

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blood cell casts is usually seen. The erythrocyte sedimentation rate (ESR) may be increased, particularly in those with an underlying systemic disease. Some lung disorders characterized by DAH are associated with the production of antineutrophil cytoplasmic antibodies (ANCA) directed against neutrophil cytoplasmic antigens or antibodies directed at the glomerular basement membrane. ANCA testing, in particular, can play an important role in the workup of DAH because it is used in the diagnosis and classification of various pulmonary vasculitides that cause DAH. Two major immunofluorescent patterns can be seen in ANCA testing: diffuse staining throughout the cytoplasm (c-ANCA) or staining around the nucleus (p-ANCA). Specific antigens that ANCAs are directed against include proteinase-3 (PR-3), typically causing the c-ANCA pattern, and myeloperoxidase (MPO), which typically causes the p-ANCA pattern. All DAH syndromes are characterized by three distinct histologic patterns. Bland pulmonary hemorrhage is due to alveolar hemorrhage without inflammation or destruction of the alveolar structures. This pattern is seen in conditions where there is elevated pulmonary capillary hydrostatic pressure, such as congestive heart failure or mitral stenosis, or with the use of certain anticoagulation medications. Diffuse alveolar damage (DAD) is caused by a variety of pulmonary infections, connective tissue diseases, and medications. DAD is also seen in acute respiratory distress syndrome (ARDS) from any etiology. Histologically, alveolar walls appear edematous and are lined with hyaline membranes. The most common histologic pattern seen on lung biopsy obtained from patients with DAH is pulmonary capillaritis, which is characterized by neutrophilic infiltration of the alveolar septa. This sequentially leads to necrosis, loss of capillary structural integrity, and extravasation of red blood cells into the interstitium and alveolar spaces. This finding is seen in a variety of connective tissue diseases and is the most common histologic pattern of the pulmonary vasculitides. The pulmonary vasculitides represent a group of specific entities, many of which are associated with elevated serum ANCA levels. These entities include Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and certain drug-induced vasculitis syndromes. Pauci-immune glomerulonephritis without evidence of extrarenal disease is a disorder that is considered to be on the spectrum of Wegener granulomatosis and microscopic polyangiitis because its histologic features are indistinguishable from these disorders and some patients eventually develop extrarenal (pulmonary) manifestations. Wegener granulomatosis is a systemic necrotizing granulomatous vasculitis that often involves the small and medium-sized vessels of the upper airway, the lower respiratory tract, and the kidney. Although this triad is not always seen at initial presentation, as only 40% of those affected have renal disease at that time, 80% to 90% of patients eventually develop glomerulonephritis. The most frequent manifestations of this illness are pulmonary, as highlighted by cough, chest pain, hemoptysis, and dyspnea. Constitutional symptoms, such as fever and weight loss, as well as symptoms due to involvement of the skin, eye, heart, nervous system, and musculoskeletal system, are also common. The diagnosis of Wegener granulomatosis is supported by clinical findings and by the presence of circulating ANCAs, which are seen in 90% of all patients. The remaining 10% are ANCA negative. In ANCA-positive patients, antibodies are

usually directed against PR-3; however, 10% to 20% may have anti-MPO antibodies. Chest imaging may show bilateral disease and infiltrates that evolve over the course of the illness. Lung nodules are common and may cavitate. Effusions and adenopathy are not common. Sinus films or CT scans serve to diagnose upper airway involvement. Tissue biopsy at a site of active disease is generally needed to confirm Wegener’s granulomatosis. The presence of granulomatous inflammation is common, but actual vasculitis is seen in only 35% of patients. A renal biopsy is preferred because it is easier to perform and more often diagnostic. In the absence of renal involvement, a lung biopsy should be considered. Pathologically, Wegener granulomatosis is characterized by small and medium vessel necrotizing vasculitis and granulomatous inflammation. Special stains and cultures should be performed to exclude the presence of infections that can produce similar findings. Microscopic polyangiitis is a form of systemic necrotizing small vessel vasculitis that universally affects the kidneys, whereas pulmonary involvement occurs in only a minority of patients (10% to 30%). This rare condition has a prevalence of 1 to 3 cases per 100,000, but it is the most common cause of pulmonary-renal syndrome. It is often heralded by a long prodromal phase, characterized by constitutional symptoms followed by the development of rapidly progressive glomerulonephritis (RPGN). In those patients who do develop lung involvement, DAH secondary to capillaritis is the most common manifestation. Joint, skin, peripheral nervous system, and gastrointestinal involvement can be seen as well. Seventy percent of patients with microscopic polyangiitis are ANCA positive, most of whom have antiMPO antibodies. Because anti-MPO and anti-PR3 antibodies can be present in both microscopic polyangiitis and Wegener granulomatosis, these diseases cannot be distinguished based on their ANCA pattern. However, the two diseases can be distinguished pathologically because microscopic polyangiitis is characterized by a focal, segmental necrotizing vasculitis affecting venules, capillaries, arterioles, and small arteries without clinical or pathologic evidence of necrotizing granulomatous inflammation. The absence or paucity of immunoglobulin localization in vessel walls distinguishes microscopic polyangiitis from immune complex– mediated small vessel vasculitis such as Henoch-Schönlein purpura and cryoglobulinemic vasculitis. Treatments of Wegener granulomatosis and microscopic polyangiitis are similar. Combination therapy with cortico steroids and cyclophosphamide is the standard of care. Azathioprine can be substituted for cyclophosphamide if remission is achieved. Intravenous immunoglobulin may be effective for those with persistent disease. Novel therapies, including trimethoprim-sulfamethoxazole, antilymphocyte monoclonal antibodies, and tumor necrosis factor inhibitors, have been tried with some success. Allergic granulomatosis or Churg-Strauss syndrome is characterized by the triad of asthma, hypereosinophilia, and necrotizing vasculitis. Many other organ systems, including the nervous system, skin, heart, and gastrointestinal tract, may be involved as well. The vasculitis can be associated with skin nodules and purpura. Although DAH and glomerulonephritis may occur, they are much less common than in the other small vessel vasculitides. Morbidity and mortality are often due to cardiac or gastrointestinal complications or

Chapter 18—Interstitial Lung Diseases to status asthmaticus and respiratory failure. ANCAs are less helpful in Churg-Strauss syndrome because only 50% of patients are ANCA positive. Anti-MPO antibodies are more commonly seen in these patients. Pathologically, both a necrotizing, small vessel vasculitis and an eosinophil-rich inflammatory infiltrate with necrotizing granulomas are seen. Most patients respond well to corticosteroids, but other immunosuppressants similar to cyclophosphamide may be required in patients with refractory disorders. Other well-known causes of pulmonary capillaritis include the systemic vasculitides, collagen vascular disorders, antiglomerular membrane antibody syndrome (Goodpasture syndrome), and Henoch-Schönlein purpura. Goodpasture syndrome causes DAH associated with glomerulonephritis caused by antiglomerular basement membrane antibodies to the α3 chain of type IV collagen that is also found in the lung basement membrane. More than 90% of patients with Goodpasture syndrome have antiglomerular basement membrane antibodies detectable in the serum. In those without circulating antibodies, the diagnosis may be confirmed by lung biopsy, although the kidney is the preferred site. Up to 40% may also be ANCA positive, primarily with anti-MPO antibodies. Pathologically, linear deposition of antibody along the alveolar or glomerular basement membrane that is visible by direct immunofluorescence occurs. The treatment of Goodpasture syndrome is plasmapheresis and immunosuppression. The disease is fatal if left untreated. Idiopathic pulmonary hemorrhage or hemosiderosis is a diagnosis of exclusion. Patients with this syndrome have recurrent DAH without associated renal or systemic disease. Histologically, the lung shows hemorrhage and hemosiderin accumulation without inflammation. Treatment includes supportive care, immunosuppression, and occasionally plasmapheresis, but response to therapy is varied. This syndrome is most common in children, who have a worse prognosis than adults.

Environmental and Occupational Interstitial Lung Diseases Several environmental and occupational exposures may cause ILDs. These include the pneumoconioses, drug-induced ILD (discussed earlier), and hypersensitivity pneumonitis. Pneumoconiosis and hypersensitivity pneumonitis are discussed later. The pneumoconioses are lung diseases resulting from the inhalation of mineral dusts, including silica, coal dust, or asbestos. Hypersensitivity pneumonitis is caused by the inhalation of organic dusts.

PNEUMOCONIOSIS The pneumoconioses result from the effects of accumulation of mineral dusts in the lungs, with the typical reaction being fibrosis. In general, the risk and extent of these diseases are related to the intensity and cumulative amount of exposure over time. Prevention of the pneumoconioses through occupational safeguards or, in the case of asbestos, legislative bans on use, is most important because there are not effective treatments for these diseases once established.

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Silicosis is a lung disease caused by exposure to crystallinefree silica, which results in an inflammatory and fibrotic reaction resulting in the characteristic silicotic nodule. Certain occupations that have a higher propensity for exposure to silica include mining, stone cutting, carving, polishing, foundry work, and abrasive clearing (sandblasting). Although exposure is usually chronic (over years), accelerated and acute disease manifestations have been described in the setting of heavier short-term exposures. Acute silicosis causes a pulmonary alveolar proteinosis, with an accumulation of surfactant in the alveolar spaces. Chronic silicosis results in simple nodular silicosis, which is usually asymptomatic unless the patient is also exposed to tobacco, and progressive massive fibrosis (PMF), which is characterized by extensive bilateral apical fibrosis resulting from the confluence of many silicotic nodules. Patients with silicosis may present with dyspnea or may be relatively asymptomatic but present for evaluation of an abnormal chest radiograph. Chest radiographs in uncomplicated silicosis show upper lobe nodular opacities, which may be subtle, whereas PMF results in marked architectural distortion of the upper lobes (Web Fig 18-7). Hilar node enlargement may be seen accompanied by eggshell nodal calcification (Web Fig 18-8). Pulmonary function tests in simple nodular silicosis may be normal or show a mixed obstructive or restrictive pattern, whereas PMF is typically associated with severe restriction and hypoxemia. Patients with silicosis are at elevated risk for tuberculosis and should be screened for latent tuberculosis infection; there is also an association between silicosis and rheumatoid arthritis. Coal worker’s pneumoconiosis is an uncommon cause of pulmonary fibrosis, occurring in workers exposed to coal dust and graphite. Usually, the patients are exposed while working in underground mines. Coal worker’s pneumoconiosis results in the formation of pigmented lesions in the lung, surrounded by emphysema, known as coal macules. PMF may subsequently occur. Most patients show chronic cough, which is usually productive, because of bronchitis related to coal exposure or to tobacco. The chest radiograph shows diffuse small rounded opacities. As with silicosis, there is an association with rheumatoid arthritis; Caplan syndrome is the occurrence of multiple large, sometimes cavitary, lung nodules in association with rheumatoid arthritis following coal dust exposure. Asbestosis is due to chronic exposure to asbestos, which is a fibrous silicate used for insulation, for friction-bearing surfaces, and to strengthen materials. The inhaled asbestos fibers are deposited in the lungs, where small fibers may be phagocytosed and cleared through lymphatics to the pleural space, but longer fibers are often retained. Typically, asbestos exposure may lead to pleural disease characterized by pleural plaques, effusion, and fibrosis, but it does not necessarily affect the lung parenchyma. If it does, it is called asbestosis and is associated with interstitial lung fibrosis. Asbestosis is characterized by a gradual onset of dyspnea. As with other pneumoconioses, the risk and severity of disease are related to the extent and duration of cumulative exposure. Asbestosis is often diagnosed after exposure has ceased, and disease progression may continue to occur in the absence of ongoing exposure, owing to the reaction to retained asbestos fibers in the lung. The clinical presentation, pulmonary function tests, and imaging studies are similar to those

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found in restrictive lung diseases like IPF. However, the detection of significant pleural disease is useful in distinguishing this illness from other ILDs. The diagnosis is made from the history and demonstration of concomitant pleural plaques and lower lobe–predominant fibrotic changes on chest radiographs or CT scan. In uncertain cases, the demonstration of asbestos in tissue specimens may be necessary; asbestos bodies are the characteristic finding and consist of asbestos fibers coated by iron-containing (ferruginous) material. Asbestos exposure results in an elevated incidence of malignancy, including lung carcinoma and mesothelioma, especially in persons who also smoke. Whether the presence of asbestosis itself confers a heightened risk for malignancy, independent of the effects of asbestos exposure alone, is uncertain. No specific treatment for asbestosis exists. Berylliosis results from exposure to beryllium, a rare metal useful in modern, high-technology industries. Exposure to beryllium can lead to an acute chemical bronchitis and pneumonitis or chronic beryllium disease. Chronic beryllium disease is characterized by a multisystemic granulomatosis that is difficult to distinguish from sarcoidosis. The diagnosis is made by history of exposure, histologic examination, and laboratory confirmation through the beryllium lymphocyte proliferation test that is available at specialized centers. Corticosteroids may be useful in the treatment of berylliosis, but patients should avoid further exposure to beryllium.

HYPERSENSITIVITY PNEUMONITIS Hypersensitivity pneumonitis (also termed extrinsic allergic alveolitis) is a relatively common ILD resulting from an exaggerated immune reaction to various inhaled organic antigens in sensitized individuals. Potential sensitizing antigens are diverse, ranging from bacterial, fungal, and animal proteins to low–molecular-weight chemicals (Table 18-7). Although evocative descriptions have been given to occupational forms of this disease (“paprika splitter’s lung” resulting from sensitivity to Mucor stolonifer), more prosaic exposures may occur in everyday life, for example, to contaminated hot tub water or to pet birds. The disease may present in an acute fashion several hours after intense exposure to a provocative antigen, with fever, chills, cough, dyspnea, and malaise that last for up to 24 hours. Subacute or chronic disease may occur with repeated or prolonged antigen exposure and may result in chronic dyspnea and cough, with eventual progression to pulmonary fibrosis. Diffuse crackles and wheezes are common physical findings. Hypoxemia may be present. In general, hypersensitivity pneumonitis is characterized by nonspecific infiltrates in the mid and upper lung fields on chest radiographs. CT scanning is more sensitive than chest radiography, revealing ground-glass opacities, centrilobular nodules, and mosaic attenuation patterns resulting from airway obstruction. In chronic hypersensitivity pneumonitis, emphysema and lower lobe honeycombing may be present. Restrictive or mixed obstructive-restrictive patterns may be seen on pulmonary function testing, along with abnormalities of gas exchange. Bronchoalveolar lavage may demonstrate a lymphocytic alveolitis, with CD8 T-lymphocyte predominance. Patients with hypersensitivity pneumonitis may have pre-

Table 18-7 Hypersensitivity Pneumonitis Antigen

Source

Disease Examples

Thermophilic bacteria

Moldy hay, sugar cane, compost

Other bacteria

Contaminated water, wood dust, fertilizer, paprika dust

Fungi

Moldy cork, contaminated wood dust, barley, maple logs

Animal protein

Bird droppings, animal urine, bovine and porcine pituitary powder

Chemically altered human proteins (albumin and others) Phthalic anhydride

Toluene diisocyanate Trimellitic anhydride Diphenylmethane diisocyanate Heated epoxy resin

Farmer’s lung, bagassosis, mushroom worker’s disease Humidifier, detergent worker’s disease, and familial hypersensitivity pneumonitis Suberosis, sequoiosis, and maple bark stripper’s disease, malt worker’s disease, and paprika splitter’s lung Pigeon breeder’s lung, duck fever, turkey handler’s disease, pituitary snuff taker’s disease, laboratory worker’s hypersensitivity pneumonitis Hypersensitivity pneumonitis

Epoxy resin lung

cipitating antibodies to the offending antigen, but serum precipitins are not sufficiently sensitive or specific for diagnosis, and the specific antigen may not be known or may not be tested for with standard test panels. An appropriate exposure, clinical history, and imaging findings can suggest the diagnosis, but lung biopsy may be necessary for confirmation. Transbronchial biopsy is often sufficient. Typical biopsy findings include poorly formed granulomas containing foreign body giant cells and interstitial chronic inflammation with a bronchiolocentric component. Clinical improvement often occurs in the hospital setting when patients are isolated from the offending antigen, and relapse may occur after discharge. Corticosteroids can relieve symptoms in the acute phase, but their efficacy in chronic forms of the disease is less clear. Identification of the cause of hypersensitivity pneumonitis is important because chronic disease management requires avoidance of exposure to the antigen, which can be financially or psychologically challenging for patients in the setting of occupational, pet, or residential exposures.

Specific Entities PULMONARY LANGERHANS CELL HISTIOCYTOSIS (EOSINOPHILIC GRANULOMA) Pulmonary Langerhans cell histiocytosis (LCH), also called eosinophilic granuloma, is a disease of young- to middle-aged adults. Nearly all cases occur in white men who smoke. The

Chapter 18—Interstitial Lung Diseases disorder results from the infiltration of Langerhans cells, which are dendritic cells, into the lung parenchyma. Smoking may alter local immune signaling, attracting the Langerhans cells to the lungs. Patients typically exhibit constitutional symptoms, dyspnea on exertion, and cough, possibly with hemoptysis. Pneumothorax may also occur. Imaging shows micronodular lesions and cysts that predominate in the mid and upper lung zones. Pulmonary function tests show an obstructive pattern and impaired diffusion capacity. Specific diagnosis can be made with open lung biopsy, which demonstrates multiple stellate lung nodules that may be cellular or fibrotic, containing Langerhans cells that stain for Cd1a and S100. Electron microscopy may reveal Birbeck granules, distinctive racquet-shaped structures within the cells. In the right clinical setting and with a typical HRCT, a biopsy might not be needed for diagnosis. In contrast to systemic LCH, pulmonary LCH is not a neoplastic disorder, and spontaneous regression may occur. The main treatment is tobacco cessation. Corticosteroids and other immunosuppressants are sometimes employed as adjunctive therapy.

LYMPHANGIOLEIOMYOMATOSIS Lymphangioleiomyomatosis (LAM) is a rare disorder that may occur in association with the tuberous sclerosis complex or sporadically in women of childbearing age. The disease is characterized by extensive nodular infiltration of the lungs and lymphatics with growths of smooth muscle–like cells. Mutations in the TSC-1 or TSC-2 gene, encoding for tumor suppressor proteins that normally act as inhibitors of protein synthesis and cell growth, may result in tuberous sclerosis or LAM, with mutations in TSC-2 being associated with greater disease severity. Dyspnea and pneumothorax are the most common presentations, with chylous pleural effusions and hemoptysis also occurring. These clinical presentations result from the lung parenchymal destruction, airway narrowing, and lymphatic obstruction caused by the abnormal proliferation of the smooth muscle–like cells. Imaging studies show an interstitial pattern with mid and upper lung predominance, multiple thin-walled cystic lesions, and characteristically preserved lung volumes. Pleural effusion or pneumothorax may also be present on imaging. CT of the abdomen may reveal fat-containing kidney lesions consistent with angiomyolipomas. Pulmonary function tests typically show a progressive obstructive pattern, although mixed obstruction and restriction may also be seen. Although the clinical features coupled with characteristic imaging are often diagnostic, lung biopsy might be necessary in some cases. This demonstrates interstitial nodules composed centrally of spindle-shaped cells that stain for smooth muscle cell actin as well as with HMB-45, an antibody to the melanocytic glycoprotein gp-100, involving the alveolar walls, lobular septa, venules, small airways, and pleura. Treatment involves management of pleural complications, including use of pleurodesis to prevent recurrent pneumo thorax or effusion; bronchodilator and oxygen therapy; and avoidance of pharmacologic estrogens, which may exacerbate the disease. Progesterones have been used in an attempt to modulate disease progression, although efficacy data are limited. Because the products of the TSC-1 and TSC-2 genes normally act as inhibitors of the mammalian target of rapamycin (m-TOR), use of inhibitors of m-TOR activity

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like sirolimus is under investigation in LAM, with sirolimus being shown in one small study to improve lung function in LAM. Lung transplantation can be performed in patients with severe pulmonary dysfunction.

EOSINOPHILIC LUNG DISEASE Eosinophilic lung diseases are characterized by the presence of pulmonary infiltrates and eosinophilia of the peripheral blood or lung. Because eosinophilia is a feature of many diseases, it is important to distinguish primary pulmonary eosinophilic lung disorders from lung disorders in which eosinophilia is secondary to a specific cause. Eosinophilic lung diseases can be categorized as follows: primary pulmonary eosinophilic disorders (including acute and chronic eosinophilic pneumonia, hypereosinophilic syndrome), pulmonary disorders of known cause associated with eosinophilia (including asthma, allergic bronchopulmonary aspergillosis, drug reactions, parasitic infections), lung diseases associated with eosinophilia (including hypersensitivity pneumonitis, COP, IPF), malignancies associated with eosinophilia (including lung cancer, leukemia, lymphoma), and systemic disease associated with eosinophilia (including rheumatoid arthritis, sarcoidosis, and Sjögren syndrome). Acute eosinophilic pneumonia is characterized by fever, a nonproductive cough, and dyspnea of less than 7 days’ duration, often leading to respiratory failure. This disease typically affects men between the ages of 20 and 40 years who are otherwise healthy. Chest imaging reveals diffuse bilateral pulmonary infiltrates. Eosinophilia is not present in the peripheral blood initially but may occur 7 to 30 days after onset. However, abundant eosinophils can be found in bronchoalveolar lavage fluid, and a level of greater than 25% of all nucleated cells is helpful in making the correct diagnosis. Although lung biopsy is typically not required to make the diagnosis, it can show eosinophilic infiltration with acute and organizing diffuse alveolar damage. Treatment with corticosteroids typically offers complete clinical and radiographic resolution without recurrence or residual sequelae. Chronic eosinophilic pneumonia is an idiopathic disease predominantly of middle-aged women. Also termed prolonged pulmonary eosinophilia, this illness is characterized by a productive cough, dyspnea, malaise, weight loss, night sweats, and fever associated with progressive peripheral lung infiltrates that, on chest radiography, have been described as resembling the “photographic negative of pulmonary edema” (Web Fig 18-9). On presentation, most patients have a peripheral eosinophilia of greater than 30% and bronchoalveolar lavage fluid eosinophilia as well. Histologic examination shows eosinophils and histiocytes in the lung parenchyma and interstitium, areas of COP, but minimal fibrosis. Spontaneous remissions have been reported, but respiratory failure can also develop. Typically, treatment with corticosteroids is rapidly effective. Prolonged therapy is recommended because unlike with acute eosinophilic pneumonia, relapses are common. Simple pulmonary eosinophilia, also known as Löffler syndrome, is characterized by transient migratory infiltrates that last less than 1 month. In some cases, no symptoms are present, but dyspnea and dry cough may occur. Pathologic examination of tissues reveals interstitial and intra-alveolar

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accumulation of eosinophils, macrophages, and edema. The syndrome might be idiopathic or caused by parasitic infections (e.g., Ascaris species, Strongyloides species, hookworms) or drugs (e.g., nitrofurantoin, minocycline, sulfonamides, penicillin, nonsteroidal anti-inflammatory drugs). Treatment requires removal of the offending agent or treatment of the parasitic infection. In idiopathic cases, corticosteroids may be used. Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction that occurs when Aspergillus species colonizes the airways in patients with asthma or cystic fibrosis. Patients may present with fever, malaise, a cough productive of thick brown mucus plugs, and occasionally hemoptysis. On chest radiograph, pulmonary infiltrates, which are often transient and migratory, and central bronchiectasis may be seen. Peripheral eosinophilia of greater than 10%, elevated IgE levels (as well as the presence of aspergillus-specific IgE), and precipitating antibodies to aspergillus are among the laboratory abnormalities seen in ABPA. Response to corticosteroids is good. Itraconazole can be added to the treatment regimen as well.

PULMONARY ALVEOLAR PROTEINOSIS Pulmonary alveolar proteinosis (PAP) is a rare disorder in which lipoproteinaceous material, similar to surfactant, accumulates within the alveoli. PAP has a congenital form,

characterized by mutations of the genes encoding surfactant protein B or C or for the receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF). Secondary PAP occurs in conditions in which there is a functional impairment or decrease in the number of alveolar macrophages, as seen in various hematologic malignancies (leukemia), infections (pneumocystis pneumonia), and inhalation of toxic dusts (silica, aluminum) or following allogeneic bone marrow transplantation. Acquired or idiopathic forms of PAP may represent an autoimmune disease, with neutralizing antibodies directly targeting GM-CSF playing a role in its pathogenesis. Patients with PAP present with progressive dyspnea on exertion, malaise, low-grade fever, and cough. Chest radiograph typically reveals bilateral perihilar opacities. CT scan may show thickening of the intralobular and interlobular septae, creating a pattern referred to as crazy paving, which is a nonspecific finding because it is seen in many other diseases of the lung. Bronchoalveolar lavage fluid can establish the diagnosis because the lavage fluid has a milky, opaque appearance that contains large “foamy” alveolar macrophages with few inflammatory cells. Asymptomatic patients and those with mild symptoms require no immediate treatment. Whole-lung lavage is indicated for patients with hypoxemia or severe dyspnea and, in up to 40% of patients, may be required only one time. GM-CSF administration in patients with acquired PAP may be beneficial, but less so than whole-lung lavage.

Prospectus for the Future Sensitive and specific noninvasive methods are needed for the early identification of ILDs when attempts at preventing progression of lung fibrosis are likely to be more effective. IPF, the most common of the IIPs, is almost invariably fatal, and current treatment strategies are ineffective. Several clinical trials are examining the effectiveness of novel drugs in its treatment, including anti–TNF-α agents, endothelin receptor antagonists, and antioxidants. The National Institutes of Health have established the Idiopathic Pulmonary Fibrosis Clinical Research Network to accelerate discovery. However, much confusion about this disease remains in the community, and educational strategies will be needed to accelerate diagnosis. Sarcoidosis is another enigmatic disease that, when progressive, is largely unresponsive to current treatment strategies. Small studies suggest agents capable of immunomodulation might be useful, but further work is needed in this area. The advent of new technology able to evaluate genetic abnormalities related to

References Allen TC: Pulmonary Langerhans cell histiocytosis and other pulmonary histiocytic diseases: A review. Arch Pathol Lab Med 132:1171-1181, 2008. Collard HR, Schwarz MI: Diffuse alveolar hemorrhage. Clin Chest Med 25;583-592, 2004. Frankel SK, Cosgrove GP, Fischer A, et al: Update in the diagnosis and management of pulmonary vasculitis. Chest 129;452-465, 2006. Ianuzzi MC, Rybicki BA, Teirstein AS: Sarcoidosis. N Engl J Med 357:2153-2165, 2007. Joint statement of the American Thoracic Society (ATS) and the European Respiratory Society (ERS): American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 165:277-304, 2002.

disease has unveiled gene polymorphisms associated with IPF and sarcoidosis, among other ILDs. However, the true role of these abnormalities in causing the disease remains unclear, and the ability to exploit this information for early detection of disease is still limited. Interesting research is ongoing related to less common ILDs such as lymphangioleiomyomatosis, which affects women of childbearing age, and is focusing on the intracellular pathways that lead to cellular dysfunction in these disorders. Further work in this area and in the detection of the environmental hazards responsible for ILD is desperately needed. Until new and effective treatment strategies are generated, lung transplantation represents the only hope for an increasing number of patients with fibrosing ILDs. Therefore, efforts to extend life in lung transplant recipients are underway, particularly those targeting chronic rejection and bronchiolitis obliterans, the main cause of death in this population.

Leslie KO: Historical perspective: A pathologic approach to the classification of idiopathic interstitial pneumonias. Chest 128(5 Suppl 1):513S-519S, 2005. Limper AH: Drug-induced pulmonary disease. In Mason R, Broaddus VC, Murray JF, Nadel JA (eds): Murray and Nadel’s Textbook of Respiratory Medicine, 4th ed. Philadelphia, Elsevier Saunders, 2005, pp 1888-1908. Krymakaya VP: Smooth muscle-like cells in pulmonary lymphangioleiomyomatosis. Proc Am Thorac Soc 5:119-126, 2008. Noth I, Martinez FJ: Recent advances in idiopathic pulmonary fibrosis. Chest 132;637-650, 2007. Trapnell BC, Whitsett JA, Nakata K: Pulmonary alveolar proteinosis. N Engl J Med. 349:2527-2539, 2003. Wechsler ME: Pulmonary eosinophilic syndromes. Immunol Allergy Clin North Am 27:477-492, 2007.

Chapter

19

IV

Pulmonary Vascular Disease Sharon Rounds

P

ulmonary vascular diseases are a heterogenous group of disorders with multiple causes. Pulmonary vascular disorders are caused by conditions that directly affect the pulmonary vessels, as in idiopathic pulmonary arterial hypertension (IPAH), or by disorders outside of the lung, as in pulmonary hypertension associated with lung disease and hypoxemia. The World Health Organization classification of pulmonary hypertensive disorders is presented in Table 19-1. The main complication of these disorders is the development of pulmonary hypertension, which is defined as mean pulmonary artery pressure over 25 mm Hg at rest or over 30 mm Hg with exercise. Factors that increase pul monary arterial pressure include cardiac output, left atrial pressure, blood viscosity, and (most importantly) loss of cross-sectional area of the vascular bed, which increases vascular resistance. The loss of a cross-sectional area may be the result of mechanical occlusion, loss of vessels, vascular remodeling, or vasoconstriction. Clinical manifestations of the disease may not be exhibited until late in the course of the disease. This delayed onset occurs because the pulmonary vasculature is a high-flow, low-resistance, highly compliant system with very high capacitance such that it can accept the entire output of the right ventricle with only slight increases in pressure—even when one half of the pulmonary vasculature is removed.

Pulmonary Thromboembolic Disease Pulmonary thromboembolic disease is a relatively common entity with an incidence ranging from 400,000 to 650,000 patients per year in the United States. Pulmonary thromboembolic disease is usually a complication of venous thrombosis. The deep veins of the femoral and popliteal systems of the lower extremities are most often affected, but right atrial, right ventricular, and upper extremity thromboses can also embolize to the lung. In view of this, predisposing factors for pulmonary embolism are the same as those

for venous thrombosis and include venous stasis, hypercoagulability, and endothelial injury. Congenital or acquired procoagulant disorders (e.g., activated protein C deficiency) are also considered predisposing factors. After a clot dislodges from the lower extremity circulation, it travels to the pulmonary circulation, where it can obstruct a branch of the pulmonary artery. The affected lung segment develops an increased ventilation-perfusion ). This increases overall dead space ventilation, ratio ( V Q which leads to an inefficient excretion of partial pressure of carbon dioxide in arterial blood (Paco2). In addition, blood flow is shifted from the obstructed site to other areas, thereby leading to which may include areas of low V Q, shunting and hypoxemia. Pulmonary infarction of the area distal to the occlusion is rare because of the redundancy of the pulmonary circulation and because of oxygenation of lung parenchyma by bronchial arteries and by alveolar oxygen.

CLINICAL PRESENTATION The classic presentation of acute pulmonary embolism includes acute shortness of breath accompanied by chest pain, hemoptysis, severe hypoxemia, and circulatory collapse as a result of shock. However, more often than not, the presentation is subtle, and the diagnosis might be difficult to make without a high level of suspicion, particularly in young individuals with otherwise healthy lungs. Dyspnea on exertion and atypical chest pain might be the only symptoms on initial presentation. Therefore, a careful history is paramount when evaluating patients for thromboembolic disease, especially those at high risk for this disorder as a result of stasis, malignancy, and previous history of venous thrombosis as well as other risk factors. The physical examination might reveal abnormalities in lung auscultation ranging from isolated crackles to diffuse wheezing. Pleural effusions might be underlying areas of dullness to percussion during the physical examination. Edema of the extremities, especially if the edema is asymmetrical, might point to venous thrombosis. In deep vein thrombosis, dorsiflexion of 241

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Section IV—Pulmonary and Critical Care Medicine History and physical examination

Table 19-1 World Health Organization Classification of Pulmonary Hypertension Group I. Pulmonary Arterial Hypertension • Idiopathic (primary) • Familial • Related conditions, e.g., collagen vascular disease, portal hypertension, systemic-to-pulmonary shunts, HIV infection • Associated with significant venous or capillary involvement: pulmonary veno-occlusive disease and pulmonary-capillary hemangiomatosis • Persistent pulmonary hypertension of the newborn Group II. Pulmonary Venous Hypertension • Left-sided atrial or ventricular heart disease • Left-sided valvular heart disease Group III. Pulmonary Hypertension associated with Hypoxemia • Chronic obstructive pulmonary disease • Interstitial lung disease • Sleep-disordered breathing • Alveolar hypoventilation disorders • Chronic exposure to high altitude • Developmental abnormalities Group IV. Pulmonary Hypertension Due to Chronic Thrombotic Disease, Embolic Disease, or Both • Thromboembolic obstruction of proximal pulmonary arteries • Thromboembolic obstruction of distal pulmonary arteries • Pulmonary embolism (tumor, parasites, foreign material)

Suspected PE

Leg Doppler or venogram

DVT

· · V/Q scan

Spiral CT

Angiogram

Low Intermediate

High probability

PE confirmed

Figure 19-1 Tests commonly used in the evaluation of patients who may have pulmonary embolism (PE). Doppler ultrasound or venogram of the leg is useful to evaluate deep vein ) scans are most thrombosis (DVT). Ventilation-perfusion ( V Q useful when they are normal or show lesions highly suggestive of intravascular clot. Unfortunately, these findings are not the case in many patients, requiring further investigation. Spiral computed tomography (CT) has high sensitivity and specificity and allows for the evaluation of thoracic structures in addition to assessing the vasculature. Angiography is considered the gold standard, but it is often not needed if other noninvasive tests are used alone or in combination.

Group V. Miscellaneous • Sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

the foot may cause calf pain as a result of stretching the calf muscles and deep veins (Homan sign). Signs of pulmonary hypertension and right ventricular strain, such as increased pulmonary component of the second heart sound or right ventricular heave, are not usually appreciated unless there is a massive pulmonary embolus or preexisting heart or lung disease.

EVALUATION In severe cases, arterial blood gas measurement may show acidemia, hypoxemia, and hypercapnia, but subtle changes such as mild alkalosis might be the only abnormalities. A normal Paco2 in a patient with tachypnea and presumably hyperventilation suggests increased dead space and, in the appropriate setting, might point to the diagnosis. However, a normal alveolar-arterial oxygen-tension gradient (A-aDo2) does not exclude acute pulmonary embolism. An elevated level of lactic dehydrogenase (LDH) might be the result of tissue infarction, but this test is also insensitive and nonspecific. Some have advocated the use of plasma D-dimer levels in patients who might have pulmonary thromboembolism, but these are not specific either because they are elevated in patients with several unrelated medical conditions such as congestive heart failure, chronic illness, and connective tissue disorders. The main usefulness of plasma D-dimer levels is its negative predictive value.

The electrocardiogram may show atrial tachyarrhythmias or evidence of right heart strain as evidenced by a new right bundle branch block, right ventricular strain pattern, and the SIQIITIII pattern that mimics inferior myocardial infarction. The chest radiograph is often normal but may show atelectasis, isolated infiltrates, or a small pleural effusion. Oligemia (Westermark sign), an abrupt cutoff of pulmonary vessels or enlarged central pulmonary arteries (Fleischer sign), and pleural-based area of increased opacity (Hampton hump) might also be noted. Independent of these findings, chest radiographs are not sensitive enough to diagnose pulmonary embolism. Three diagnostic methods are used for scan, chest the diagnosis of pulmonary embolism: the V Q computed tomography (CT), and pulmonary arteriography scan compares lung ventilation by (Fig. 19-1). The V Q radiolabeled tracer gas with lung perfusion by radiolabeled scan micro-occlusive particles. The usefulness of the V Q depends greatly on the pre-test probability of the disease, which, in turn, is dependent on the expertise of the clinician scan and his or her level of certainty. A high-probability V Q is characterized by lobar or multilobar perfusion defects that coincide with areas of normal or relatively normal ventilation and is more than 90% accurate in diagnosing pulmo scan shows no perfusion or nary embolism. A normal V Q ventilation defects and can exclude pulmonary embolism in essentially all cases. However, the test is less reliable when interpreted as low, intermediate, or indeterminate probability. Under such circumstances, pulmonary embolism is likely in between 4% and 66% of patients (Table 19-2), and further testing is necessary for an accurate diagnosis of pulmonary embolism.

Chapter 19—Pulmonary Vascular Disease Table 19-2 Pulmonary Embolism Likelihood Using Clinical Suggestion and Ventilation-Perfusion Scan Scan Result High Intermediate Low Normal All scans

Clinical Probability

80%-100% 96 66 40 0 68

20%-79% 0%-19% All 88 28 16 6 30

56 16 4 2 9

87 30 14 4 28

Data from The PIOPED Investigators: Value of ventilation/perfusion scan in acute pulmonary embolism: Results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA;263:27532759, 1990.

Spiral CT angiography provides a noninvasive and sensitive way to evaluate for pulmonary emboli (Web Fig. 19-1). Pulmonary arteriography is the gold standard and should be considered in patients without contraindications to the procedure when other tests are inconclusive and a high likelihood of pulmonary embolism exists. Although complication rates related to this procedure are low, the complications are significant if developed, ranging from pulmonary hypertension and sudden death to idiosyncratic hypersensitivity reactions to dye. For this reason, many clinicians rely on a combination of interventions to arrive at the diagnosis, particularly when pulmonary tests are combined with tests that evaluate the deep veins of the lower extremities such as venography and Doppler ultrasound.

MANAGEMENT Pulmonary embolism is treated with supportive measures directed at sustaining organ function (e.g., fluid replacement for hypotension, mechanical ventilation for respiratory failure). To date, the only mechanical way to dislodge reliably a pulmonary artery clot is with surgical thromboembolectomy, a procedure with high mortality that requires a high level of expertise. Thromboembolectomy is only used for proximal clots that are long-standing (chronic thromboembolism syndrome). Consequently, medical treatments are preferred, and these are directed to prevent further clotting or to dissolve an existing clot. Anticoagulation with regular or low–molecular-weight heparin is recommended in patients without major contraindications to anticoagulation (e.g., upper gastrointestinal bleeding, hemorrhagic stroke). Their administration through subcutaneous injection appears to be as efficient as intravascular administration. The use of thrombolytic medications (e.g., tissue plasminogen activator) is usually reserved for patients with increased risk for mortality as a result of circulatory collapse caused by obstruction to the flow in large or multiple pulmonary vessels.

Idiopathic Pulmonary Arterial Hypertension IPAH is an uncommon disorder that is progressive and usually fatal without treatment. The median survival after

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the diagnosis of the disease is about 3 years without treatment. Variables associated with poor survival include heart failure, Raynaud phenomenon, elevated right atrial pressure, significantly elevated mean pulmonary arterial pressure, and decreased cardiac index. The peak incidence of IPAH is between the ages of 20 and 45 years, and it affects women more frequently than men. The cause of IPAH is unknown. However, some cases occur in families, termed familial pulmonary arterial hypertension (FPAH). The genetic cause of FPAH has been determined and is due to mutations in bone morphogenetic protein receptor type 2 and related receptors in the transforming growth factor-β family. Some cases of pulmonary arterial hypertension are associated with other disorders, such as HIV infection, scleroderma, hepatic cirrhosis, and anorectic drug use (see Table 19-1). The histologic characteristics of IPAH are changes in both the arterial and venous systems. The arteries are more commonly affected, with changes in intima, media, and adventitia. There is medial vascular smooth muscle hypertrophy, adventitial thickening, and in situ thromboses of small pulmonary arteries. Plexogenic pulmonary arteriopathy is the classic pathologic finding in pulmonary arterial hypertension, consisting of medial hypertrophy, intimal proliferation and fibroelastosis, and necrotizing arteritis. The plexiform lesion is an abnormal proliferation of pulmonary endothelial cells with slitlike channels (Web Fig. 19-2). Like pulmonary thromboembolism, the clinical presentation of IPAH can be subtle. The usual symptoms are dyspnea on exertion or chest pains, not typical of angina pectoris. In more severe cases, patients may present with syncope on exertion caused by inability of the restricted pulmonary circulation to accommodate increased cardiac output with exercise. Chest radiographs may reveal prominent pulmonary arteries or right ventricular enlargement (Web Fig. 19-3). Pulmonary function tests are usually normal, with the exception of decreased diffusing capacity, reflecting the restricted circulation and decreased surface area available for gas exchange. Indeed, the diagnosis of IPAH is dependent on exclusion of other underlying heart or lung diseases that might result in pulmonary hypertension. Echocardiogram is useful to exclude heart diseases that increase pulmonary venous pressures (e.g., mitral valve stenosis). In addition, echocardiogram may reveal enlarged right atrial and right ventricular cavity size and encroachment of the interventricular septum on the left ventricle (Web Fig. 19-4). Furthermore, echocardiogram may be used to estimate the level of pulmonary artery systolic pressure. The definitive diagnosis of IPAH requires right heart catheterization with measurement of pulmonary artery pressures and resistance. Modern treatment of IPAH improves survival and includes drugs with vasodilator activity such as calcium channel blockers and prostacyclin. Because of the potential adverse effects of calcium channel blockers (decreased preload leading to acute hypotension), continuous intravenous prostacyclin is considered the most effective medical treatment. Other vasodilator drugs now available include endothelin receptor antagonists (e.g., bosentan) and drugs increasing cyclic guanosine monophosphate because of phosphodiesterase inhibition (e.g. sildenafil). These oral agents, plus inhaled or subcutaneous prostacyclin preparations, have dramatically enhanced treatment options for

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patients with IPAH. In addition to effects on relaxing vascular smooth muscle constriction, vasodilator drugs also appear to stabilize or reverse vascular remodeling in IPAH. Other interventions include supplemental oxygen, anticoagulation, and judicious use of diuretic medications. Heartlung, double-lung, or single-lung transplantations have been performed in these patients with some success, but the overall 5-year survival rate in all patients undergoing lung transplantation is only 50%.

monary hypertension. For example, alveolar hypoxia causes intense pulmonary vasoconstriction. Long-standing hypoxia causes vascular remodeling that is similar to plexogenic pulmonary arteriopathy, but does not include in situ thromboses or formation of plexiform lesions (Web Fig. 19-5). Treatment of secondary pulmonary hypertension is directed at the underlying heart or lung disease. If hypoxia is present, home oxygen therapy should be used.

Secondary Pulmonary Hypertension

Cor Pulmonale

As shown in Table 19-1, pulmonary hypertension is also associated with other disorders that increase pulmonary venous pressure (e.g., mitral valve stenosis) and diseases of the lungs associated with hypoxemia (e.g., sleep apnea and chronic obstructive pulmonary disease. These conditions are frequently termed secondary pulmonary hypertension. Both vasoconstriction and vascular remodeling contribute to increased pulmonary vascular resistance in secondary pul-

It is now recognized that the most frequent cause of death in patients with IPAH is right ventricular failure, also termed cor pulmonale. Prolonged increased afterload causes the right ventricle to hypertrophy and then dilate. The interventricular septum shifts to the left, and filling of the left ventricle is decreased, with subsequent decreased cardiac output. Dilation of the right atrium causes atrial tachyarrhythmias and further decreased cardiac output. Treatment of cor pulmonale is directed at treatment of the underlying cause of pulmonary hypertension.

Prospectus for the Future Translational research has markedly enhanced understanding of the pathogenesis of pulmonary hypertensive disorders, and this has resulted in development of therapies that increase quality of life and improve mortality. There is increased appreciation of the role of increased vascular cell proliferation in the development of pulmonary vascular remodeling. In particular, abnormal proliferation of pulmonary endothelial cells and development of plexiform lesions have raised the suggestion that IPAH might be a disease of hyperproliferative pulmonary endothelium. In addition, little is understood regarding the

References Farber HW, Loscalzo J: Pulmonary arterial hypertension. N Engl J Med 351:16551665, 2004. Humbert M, Sitbon O, Simonneau G: Treatment of pulmonary arterial hypertension. N Engl J Med 351:1425-1436, 2004.

adaptive changes of the right ventricle to chronically increased afterload. Future investigations are needed to understand and better treat cor pulmonale. In contrast, less new information is available about pulmonary thromboembolic disease. Although new inhibitors of the coagulation cascade are currently under investigation, understanding of the mechanisms that lead to this illness has not dramatically changed during the past decade. Studies are needed in the area of genetic predisposition for thromboembolic disease as well as in vascular dysfunction leading to thrombus formation.

Newman JH, Phillips JA III, Loyd JE: Narrative review: The enigma of pulmonary arterial hypertension: New insights from genetic studies. Ann Intern Med 148:278-283, 2008. Tapson VF: Acute pulmonary embolism. N Engl J Med 358:1037-1052, 2008.

Chapter

20

IV

Disorders of Respiratory Control Sharon Rounds and Matthew D. Jankowich

D

uring the transition between wakefulness and sleep, input from the behavioral control system decreases, the hypoxic drive to breathing is reduced, and the ventilatory response to partial pressure of carbon dioxide in arterial blood (Paco2) is diminished. These changes are most dramatic during rapid eye movement (REM) sleep. Sleep-disordered breathing refers to a diverse group of conditions in which these physiologic variations are heightened, resulting in abnormal respiratory function and fragmented sleep. Of the sleep-related disorders, sleep apnea has received the most attention. Apnea is defined as the complete cessation of airflow for 10 seconds or longer. Hypopnea is a significant decrease in airflow. Occasional episodes of apnea and hypopnea are expected during normal sleep, and their frequency increases with age. However, in patients with sleep apnea, the frequency and duration of the episodes are increased, leading to sleep fragmentation and to hypoxemia and hypercapnia. Upper airway obstruction (i.e., obstructive sleep apnea [OSA]) or decreased central respiratory drive (i.e., central sleep apnea) may be the cause of sleep apnea. In some patients, both disorders are present. Some studies suggest that the prevalence of sleep-disordered breathing may be as high as 9% in women and 24% in men, but prevalence levels depend on the definition used. Sleep-disordered breathing is usually defined as a respiratory disturbance index or frequency of abnormal respiratory events that number at least five episodes per hour of sleep. Higher prevalence estimates occur in the older adult population, with some studies showing more than 80% prevalence in older patients. Children are also affected, although less frequently (about 2%).

Obstructive Sleep Apnea OSA is the most common of the sleep apnea syndromes and is considered to affect close to 6% of middle-aged and older men; it is less common in women. In these patients, the upper airway relaxation that occurs during sleep is such that complete occlusion of the airway results, and, consequently,

cessation of airflow occurs. After variable periods of airway occlusion, the patient arouses, re-establishes muscle tone, and opens the airway. This vicious cycle is repeated many times during the night, resulting in recurring episodes of hypoxemia. During airway occlusion, sympathetic tone is increased, resulting in vasoconstriction and hypertension, which persists during the waking hours. Indeed, OSA is the most common identifiable cause of systemic hypertension. With airway occlusion, intrathoracic pressure becomes more negative with inspiration. Episodes of hypoxemia can be associated with bradycardia and cardiac arrhythmias. These events are believed to be linked mechanistically to the increased incidence of stroke and coronary artery disease in patients with OSA. An important physiologic consequence of airway occlusion is arousal from sleep, resulting in fragmented sleep. Because apneas are more frequent during REM sleep, patients complain of lack of refreshing sleep. Patients with OSA have an increased incidence of motor vehicle crashes, presumably related to somnolence while driving. Interestingly, patients with OSA display an increased incidence of diabetes mellitus and other manifestations of the metabolic syndrome. The cardiovascular complications of OSA appear to be at least partially reversible with treatment of OSA.

CLINICAL MANIFESTATIONS The diagnosis of OSA is suggested when patients complain of morning headaches, recurrent awakenings, and daytime somnolence that affects daytime activities, including driving. Complaints of snoring and gasping episodes may be elicited from sleeping partners. Difficulties in maintaining sleep as a result of frequent awakenings may lead to mood effects and decreased quality of life. Recent weight gain, sedatives and sleeping pills, or alcohol intake may heighten these symptoms. The primary risk factors for OSA are obesity (although variable) and abnormal upper airway anatomy caused by macroglossia, long soft palate and uvula, enlarged tonsils, or micrognathia. Increased neck diameter (>17 cm in men and 245

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>16 cm in women) may also be noted. A narrow oropharynx as a result of a small pharyngeal opening or redundant soft tissue is often observed. Patients may be hypertensive and, in extreme cases, may show right-sided heart failure, which results as a consequence of prolonged episodes of hypoxemia and pulmonary vasoconstriction leading to pulmonary hypertension.

EVALUATION Chest radiographic images and pulmonary function testing are usually not helpful in the evaluation of patients with sleep apnea. In some cases, OSA is associated with the obesity-hypoventilation syndrome, which is characterized by significant obesity associated with chronic hypoventilation and hypoxemia (pickwickian syndrome). In such cases, arterial blood gases show hypoxemia and hypercapnia, and blood cell counts might suggest polycythemia. Although rare, hypothyroidism, acromegaly, and amyloidosis can cause or enhance OSA, and these conditions should be considered. A formal diagnosis requires overnight polysomnography during which continuous recordings of electrocardiographic and electroencephalographic tracings are made while the patient sleeps. In addition, airflow, oxygen saturation, and respiratory, eye, chin, and limb muscle movements are monitored and recorded. OSA is diagnosed in sleeping patients (confirmed by the electroencephalographic tracings) who develop cessation of airflow despite repeated muscular efforts to breathe (Web Fig. 20-1). These episodes may be accompanied by transient hypoxemia and cardiac arrhythmias. A score is derived from these data that defines clinically significant sleep apnea. Polysomnography will distinguish OSA from central sleep apnea, during which cessation of airflow is associated with halted respiratory movements. Polysomnography is also important to rule out other sleep disturbances, such as insomnia, narcolepsy, and parasomnias, as well as restless leg syndrome. Treatment of sleep apnea includes behavioral and medical approaches. When associated with obesity, weight loss should be enthusiastically encouraged. Avoidance of sedatives and alcohol is also important. Airway obstruction can be prevented with the use of continuous positive airway pressure (CPAP) provided through a tightly fitted mask. CPAP maintains positive airway pressure throughout expiration, thereby preventing collapse of the upper airway. The amount of pressure needed can be titrated, and oxygen can be added to further prevent hypoxemic episodes. CPAP is effective in most patients, but compliance with this technique is variable. Surgical removal of obstructing tonsils, adenoids, and polyps or uvulopalatopharyngoplasty may be useful in patients with specific anatomic abnormalities. A permanent tracheostomy may be necessary in severe cases when other approaches fail. However, in general, the surgical

approach to this disorder is limited to select patients only after CPAP has failed.

Other Disorders Related to Respiratory Control Central sleep apnea is a rare disorder. It predominates in men and is generally associated with normal body habitus. Patients may complain of daytime sleepiness and insomnia with frequent awakenings. This disorder is due to apnea or hypopnea, resulting from decreased central respiratory drive, and may be a consequence of central nervous system injury (i.e., central apnea may be the result of a structural abnormality of the brainstem) or idiopathic. Affected individuals may hypoventilate even while awake, although they are capable of normal voluntary breaths. During sleep, frequent apnea is common. In patients with obstructive lung disease, increased work of breathing eventually makes it difficult to maintain sufficient ventilation to maintain normal levels of Paco2. When ventilatory capacity declines, hypoventilation causes Paco2 to increase; the kidneys respond by retaining bicarbonate to keep arterial blood pH at normal levels. These patients appear to have normal ventilatory drive, but they lack the ability to increase minute ventilation to meet increased metabolic demand. This characteristic is observed in certain patients with chronic bronchitis who exhibit the classic description of the “blue bloater.” Lower brainstem and upper pontine lesions may cause central hyperventilation. However, this disorder rarely occurs in the absence of other physiologic or chemical abnormalities. Hepatic cirrhosis and extreme anxiety are all causes of central hyperventilation. Pregnancy can also cause hyperventilation and is thought to be caused by elevated levels of progesterone and other hormones that increase central actions. Apneustic breathing consists of sustained inspiratory pauses, resulting from damage to the mid-pons, most commonly caused by basilar artery infarction. Biot respiration or ataxic breathing is a haphazardly random pattern of sleep and is characterized by shallow breaths; a disruption of the respiratory rhythm generator in the medulla causes this sign. The regular cycling of crescendo-decrescendo tidal volumes, separated by apneic or hypopneic pauses, characterizes Cheyne-Stokes respiration. Patients with this disorder usually have generalized central nervous system disease or congestive heart failure. Heart failure prolongs circulatory times, causing a delay between changes in blood gases at the tissue level and the arrival of those changes at the brainstem chemoreceptors. This delay sets up a cycle of gradual increase to hyperventilation, followed by gradually decreasing ventilation to apnea, and then a repetition of the cycle. Recent studies suggest that OSA and Cheyne-Stokes respiration not only are consequences of congestive heart failure but also contribute to progression of CHF.

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Prospectus for the Future With more than 5% of the population in the United States suffering from sleep-disordered breathing, and with the recognition that these disorders may contribute to systemic illnesses such as hypertension and cardiovascular disorders, interest in early diagnosis and treatment of disorders of respiratory control is growing. In view of the high incidence and potential health consequences of sleep-disordered breathing, physicians must be on the lookout for this condition. The increased inci-

References Arzt M, Bradley TD: Treatment of sleep apnea in heart failure. Am J Resp Crit Care Med 173:1300, 2006. Caples SM, Gami AS, Somers VK: Obstructive sleep apnea. Ann Intern Med 142:187-197, 2005. Somers VK, White DP, Amin R, et al: Sleep apnea and cardiovascular disease. J Am Coll Cardiol 52:686, 2008.

dence of OSA parallels that of obesity in the United States, a public health problem that has been associated with asthma and increased risk for death. It is highly likely that genetic predisposition to OSA accounts for increased incidence in some families. Sleep medicine is an emerging clinical and research area that will continue to receive great attention in the coming decade.

Stephen GA, Eichling PS, Quan SF: Treatment of sleep disordered breathing and obstructive sleep apnea. Minerva Med 95:323-336, 2004. White DP: Pathogenesis of obstructive and central sleep apnea. Am J Resp Crit Care Med. 172:1363, 2005. Young T, Skatrud J, Peppard PE: Risk factors for obstructive sleep apnea in adults. JAMA. 201:2013, 2004.

IV

Chapter

21

Disorders of the Pleura, Mediastinum, and Chest Wall F. Dennis McCool

Pleural Disease The pleura is a thin membrane that covers the entire surface of the lung as well as the inner surface of the rib cage, diaphragm, and mediastinum. There are two pleural membranes: the visceral pleura, which covers the lung; and the parietal pleura, which lines the rib cage, diaphragm, and mediastinum. A layer of mesothelial cells lines both pleural surfaces. The closed space in between the surface of the lung and the chest cavity is referred to as the pleural space. A small amount of fluid normally resides in this space and forms a thin layer between the pleural surfaces. Pleural fluid serves as a lubricant for the visceral and parietal pleura as they move against each other during inspiration and expiration. The blood vessels in the visceral pleura are supplied from the pulmonary circulation and have greater hydrostatic pressure than the blood vessels in the parietal pleura, which are supplied by the systemic circulation. The pressure within the pleural space is subatmospheric during quiet breathing. Fluid is filtered from the higher-pressure vascular structures into the pleural space. The normal fluid turnover is about 10 to 20 mL per day with 0.2 to 1 mL remaining in the pleural space. Pleural fluid usually contains a small amount of protein and a small number of cells that are mostly mononuclear cells. Although both the parietal and visceral pleura contribute to pleural fluid formation, most of the fluid results from filtration of the higher-pressure vessels supplying the parietal pleura. After the fluid enters the pleural space, it is drained from the pleural space by a network of pleural lymphatics located beneath the mesothelial mono layer. The lymphatics originate in stomas on the parietal pleural surface. Under abnormal circumstances, fluid can accumulate in the pleural space. Factors that promote the entry of fluid into the pleural space include an increase in systemic venous pressure, an increase in pulmonary venous pressure, an increase in permeability of pleural vessels, or a 248

reduction in pleural pressure. Conditions that increase hydrostatic pressure can be seen with congestive heart failure; changes in pleural membrane permeability can be seen in varied inflammatory states; and a reduction in pleural pressure can be seen with atelectasis. Occasionally, micro vascular oncotic pressure may be sufficiently reduced to promote fluid entry into the pleural space in patients with hypoalbuminemia. Factors that block lymphatic drainage and interfere with the egress of fluid from the pleural space include central lymphatic obstruction or obstruction of lymphatic channels at the pleural surface by tumor.

PLEURAL EFFUSION Pleural effusion is the accumulation of fluid in the pleural space. Pleural effusions are generally detected by chest radiography; however, the volume of fluid in the pleural space needs to exceed 250 mL to be visualized on a chest radiograph. When an effusion is present, there is blunting of the costophrenic angle on a posteroanterior chest film; this is a fluid meniscus that can be detected posteriorly also on the lateral chest radiograph, and occasionally fluid can be demonstrated in either the minor or major fissures (Web Figs. 21-1 and 21-2). Changes in the contour of the diaphragm may signify a subpulmonic effusion. A decubitus chest radiograph can be obtained to determine whether the fluid is free-flowing or loculated. A computed tomography (CT) scan of the chest provides better definition of the pleural space than plain radiography. Chest CT is particularly useful in differentiating pulmonary parenchymal abnormalities from pleural abnormalities, defining loculated effusions, distinguishing between atelectasis and effusion, and distinguishing loculated effusion from lung abscess (Web Fig. 21-3). The edge of a lung abscess usually touches the chest wall and forms an acute angle whereas that of an empyema is usually an obtuse angle.

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Table 21-1 Pleural Effusions Transudates Congestive heart failure Hypoalbuminemia Nephrotic syndrome Malnutrition Cirrhosis Intra-abdominal fluid Ascites Peritoneal dialysis

Exudates Infection Empyema Parapneumonic Malignancy Primary lung cancer Lymphoma Metastatic cancer Pulmonary embolism and infarction Collagen vascular disease

Systemic lupus erythematosus Rheumatoid arthritis Intra-abdominal pathologic abnormalities Pancreatitis Subphrenic abscess Complications of abdominal surgery Meigs syndrome Urinothorax

Trauma Hemothorax Chylothorax Ruptured esophagus Miscellaneous Myxedema Uremia Asbestosis Lymphedema Drug-induced lupus Dressler syndrome

From Light RW, Macgregor MI, Luchsinger PC, et al: Pleural effusions: The diagnostic separation of transudates and exudates. Ann Intern Med 77:507513, 1972.

Thoracentesis is a procedure in which fluid is aspirated from the pleural space. Ultrasound or a CT scan can be used to help direct the thoracentesis catheter into collections of fluid that are otherwise difficult to drain. Analysis of pleural fluid may provide a definitive diagnosis; however, even without a definitive diagnosis, pleural fluid analysis can be useful in excluding other possible causes of disease such as infection. Classifying pleural effusions as transudates or exudates greatly assists with the differential diagnosis. The general approach to pleural effusions is outlined in Web Figure 21-4.

TRANSUDATES Effusions that accumulate due to changes in osmotic and hydrostatic forces usually have low protein states and are considered transudates (Table 21-1). Congestive heart failure is the most common cause of a transudate. With heart failure, the effusions are typically bilateral. If the effusion is unilateral, it involves the right hemithorax in most instances. Effusions due to heart failure are related to dysfunction of the left side of the heart, not the right side of the heart. Transudative effusions also may be seen in cirrhosis, nephrotic syndrome, myxedema, pulmonary embolism, superior vena cava obstruction, and peritoneal dialysis. In patients with cirrhosis, the effusions are often right sided, and the mechanism may be related to flow from the peritoneal space across diaphragmatic defects into the pleural space. Transudative effusions are typically small and rarely require drainage to improve symptoms.

EXUDATES Exudative effusions occur when there is an alteration in vascular permeability and can be observed in inflammatory states, with infection, or with neoplasm. To distinguish an exudate from a transudate, one of three criteria must be fulfilled: (1) pleural fluid–to–serum protein ratio is greater than 0.5; (2) pleural fluid–to–serum lactate dehydrogenase (LDH) ratio is greater than 0.6; and (3) pleural fluid LDH is greater than two thirds the upper limit of normal (Table 21-2). When all three criteria are met, the sensitivity, specificity, and predicted value exceed 98% for an exudative effusion. Measuring pleural fluid cholesterol may also help

Table 21-2 Differentiation of Exudative and Transudative Pleural Effusions Exudate

Transudate

Protein Pleural and serum protein LDH

>3 g/dL >0.5

125 beats per minute); tachypnea (>30 breaths per minute); high fever (>38.3° to 40° C); hypotension (systolic blood pressure < 90 mm Hg); hypoxia (Sao2 < 90% or Pao2 < 60 mm Hg); multilobar involvement on chest radiograph; and identification of highrisk pathogens such as gram-negative organisms and S. aureus. For hospitalized patients, initial therapy for community-acquired pneumonia usually includes a cephalosporin such as ceftriaxone or cefuroxime, with or without a macrolide. Antibiotic treatment should be given as soon as possible because mortality can increase even after a short delay (>8 hours) in receiving appropriate antibiotics. Sputum and blood cultures should be obtained before instituting antibiotic therapy.

Adapted from Modai J: Empiric therapy of severe infections in adults. Am J Med 88:12S-17S, 1990.

Nosocomial Pneumonia community-acquired pneumonia is designed to cover this organism (see later). M. pneumoniae is a slow-growing, facultative anaerobic organism that accounts for 25% to 60% of all atypical pneumonias. M. pneumoniae is a common cause of pneumonia in patients between the ages of 5 and 35 years who may initially exhibit upper respiratory tract symptoms, pharyngitis, and bullous myringitis. Dry cough, fever, gastrointestinal symptoms, headache, and myalgias are common. Uncommon complications include cold agglutinin–induced hemolysis, hepatitis, erythema multiforme, the syndrome of inappropriate antidiuretic hormone, pericarditis, myocarditis, and neurologic abnormalities. The chest radiograph may show fine interstitial reticulonodular infiltrates in patients, which are often relatively asymptomatic. The diagnosis is based on clinical and epidemiologic features. Acute and convalescent serologic findings are required to confirm the diagnosis, but are not helpful during the acute illness. Other common causes of community-acquired pneumonia are C. pneumoniae and Haemophilus influenzae. Patients with co-morbid conditions and those older than 65 years are also at risk for pneumonia from Legionella species, Staphylococcus aureus, and gram-negative organisms. Anaerobic infection should be considered when large amounts of oropharyngeal secretions are aspirated and in patients with chronic infections in the gingivodental crevice. Diagnostic tests for community-acquired pneumonia should include a chest radiograph and complete blood count. The role of routine sputum and blood cultures in this setting is controversial. The recommended treatment for community-acquired pneumonia is a course (7 to 10 days) of a macrolide antibiotic (erythromycin, clarithromycin, or azithromycin). If there are co-morbidities such as chronic heart or lung disease, an extended spectrum fluoroquinolone (e.g., levofloxacin, moxifloxacin, or gemifloxacin) or a β lactam (amoxicillin) plus a macrolide should be used. The choice of treatment should also be influenced by local antibiotic resistance patterns.

Nosocomial pneumonia is pneumonia that occurs after hospitalization. Nosocomial pneumonia is subdivided into three categories: hospital-acquired pneumonia (HAP); ventilator-associated pneumonia (VAP); and health care– associated pneumonia (HCAP). HAP is defined as pneumonia that occurs 48 hours or more after admission and that did not appear to be incubating at the time of admission. VAP is a type of HAP that develops more than 48 to 72 hours after endotracheal intubation. HCAP is defined as pneumonia that occurs in a nonhospitalized patient with extensive health care contact. This includes recent hospitalization, residence in a nursing home or other long-term care facility, and recent intravenous therapy. These patients should be considered at high risk for resistant organisms and therefore inappropriate for routine, empirical therapy for community-acquired pneumonia. Nosocomial pneumonia is the second most common infection in hospitalized patients and the most common infection in the intensive care unit. The pathogenesis of nosocomial pneumonia is based on colonization of the oropharynx and stomach with virulent pathogens and the subsequent aspiration of these organisms into the lower respiratory tract. Gastric colonization by gram-negative organisms is enhanced by neutralization of gastric acidity. In the first 5 days of hospitalization, H. influenzae, S. pneumoniae, and S. aureus are often isolated. After this time, pneumonia is often caused by Pseudomonas aeruginosa, S. aureus, anaerobic microbes, Acinetobacter species, and various gram-negative enteric bacilli. This finding has important therapeutic implications because these organisms are more commonly associated with multidrug antibiotic resistance. Treatment is dependent on combined chemotherapy with β lactam antipseudomonal penicillin or cephalosporin, together with an aminoglycoside or a quinolone. Vancomycin is added if methicillin-resistant S. aureus is suspected. A more definitive identification of organisms and their sensitivity to antibiotics is often sought in these patients using more invasive measures, including endotracheal

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aspirate in intubated patients or flexible fiberoptic bronchoscopy. However, the best predictor of patient outcome with nosocomial pneumonia appears to be adequacy of the initial empirical antibiotic regimen.

Complications of Pneumonia Parapneumonic effusion is a neutrophilic exudative effusion adjacent to a lung with pneumonia (Web Fig. 22-2). It can resolve with antibiotics alone or can require drainage in addition to antibiotics. As a pneumonia progresses, inflammatory pulmonary liquid leaks into the pleural space, first appearing as an uncomplicated effusion. At this point, the effusion will resolve with antibiotic therapy alone. As bacteria and inflammatory cells follow, the inflammatory process is marked by anaerobic metabolism, cytokine production, fibrin deposition in the pleural space, and thickening of the pleura. There is no universally accepted definition of empyema. However, most clinicians include in the term empyema all pleural effusions that are grossly purulent or contain microorganisms identified by a positive Gram stain or culture. Empyema must always be treated with pleural drainage, usually by a chest thoracostomy tube. Highly inflammatory parapneumonic effusions may behave as if they are infected, although microorganisms are never identified. There have been effusions described as “complicated” parapneumonic effusions, and these are identified clinically by a pH of less than 7.1 and a glucose level of less than 40 mg/dL. It is important to recognize that complicated effusions generally require drainage in addition to antibiotic therapy. The major risk factor for the development of lung abscess is aspiration resulting in a more indolent, polymicrobial infection, usually involving both aerobes and anaerobes. Conditions predisposing patients to aspiration, such as alcoholism, seizures, or stroke, are associated with an increased incidence of lung abscess. The presence of poor dentition increases the anaerobic bacterial load in the mouth and thus the likelihood of infection after an aspiration event. For aspiration-related infection, the antibiotic chosen should reflect the predominance of anaerobes. In trials of empirical therapy for lung abscess, clindamycin showed superiority over penicillin, probably because the incidence of penicillinresistant anaerobes in lung abscesses is 15% to 20%. Antibiotics should be continued for 6 weeks, and drainage should be reserved for very large abscesses or failure to resolve with antibiotics.

existed. An estimated 1.87 million individuals die from TB each year, and the global case-fatality rate was 23%, with 50% in some African countries with high HIV rates. In the United States, TB increased at an alarming rate in the early 1990s as a result of the surge of HIV infection, drug abuse, inner-city poverty, and homelessness. TB infection occurs when aerosolized, contaminated droplets (expectorated by a diseased person) are inhaled by another individual and the droplet or droplet nuclei reaches an alveolus. This is almost always a latent infection, called latent tuberculosis infection (LTBI). If the innate immune system of the host fails to eliminate the latent infection, the bacilli proliferate inside alveolar macrophages and kill the cells. The infected macrophages produce cytokines and chemokines that attract other phagocytic cells, including monocytes, other alveolar macrophages, and neutrophils, which eventually form a nodular granulomatous structure called the tubercle. If the bacterial replication is not con trolled, the tubercle enlarges, and the bacilli enter the local draining lymph nodes. This leads to lymphadenopathy, a characteristic manifestation of primary TB. The lesion produced by the expansion of the tubercle into the lung parenchyma and lymph node involvement is called the Ghon complex. The bacilli continue to proliferate until an effective cell-mediated immune (CMI) response develops, usually 2 to 6 weeks after infection. Failure by the host to mount an effective CMI response and tissue repair leads to progressive destruction of the lung. Bacterial products, tumor necrosis factor-α, macrophage antimicrobial effector molecules such as reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), and the contents of cytotoxic cells (granzymes, perforin) all can contribute to the development of caseating necrosis that characterizes a tuberculous granuloma (Fig. 22-1). If mycobacterial growth is unchecked, the bacilli may spread hematogenously to produce disseminated TB. Miliary

Mycobacterium Tuberculosis Infection Infection with Mycobacterium tuberculosis, an aerobic, nonmotile, acid-fast rod with niacin production, causes TB. In 1997, the World Health Organization Global Surveillance and Monitoring Project estimated 8 million new cases per year of TB, including 3.5 million cases of infectious pulmonary disease. In addition, 16.2 million cases of the disease

Figure 22-1 Necrotizing granuloma in lung infected with Mycobacterium tuberculosis.

Chapter 22—Infectious Disease of the Lung TB is a disseminated form with lesions resembling millet seeds. Bacilli can also spread mechanically by erosion of the caseating lesions into the lung airways. It is at this point that the host becomes infectious to others. If untreated, 80% of patients will die. Others will develop chronic disease or recover spontaneously. The chronic disease is characterized by repeated episodes of spontaneous healing with fibrotic changes around the lesions and tissue breakdown. Healing by complete spontaneous eradication of the bacilli is rare. Reactivation TB results when the persistent bacteria in a host suddenly proliferate. Only 5% to 10% of patients with no underlying medical problems who become infected develop reactivation disease in their lifetime. Although immunosuppression is clearly associated with reactivation TB, it is not clear what host factors specifically maintain the infection in a latent state for many years and what triggers the latent infection to become overt. The diagnosis of latent TB infection is dependent on a positive tuberculin test, which does not necessarily indicate active disease, but only previous infection. The standard Mantoux test is an intradermal injection of 0.1 mL (5 tuberculin units) of purified protein derivative (PPD) tuberculin in the skin of the forearm. The injection site is evaluated 48 to 72 hours later. The reading is based on the diameter of the indurated or swollen area. Patients are at high risk for developing active TB early after tuberculin conversion, and thus treatment is recommended for LTBI. The risk for active disease is 5% within 2 years of exposure and another 5% per year thereafter. HIV patients are an exception and have a 40% risk for active disease within several months of conversion. The current recommendations as to what constitutes a positive PPD test take into account the degree of clinical suspicion of LTBI (Table 22-2). Treatment of patients suspected of having active disease includes at least four drugs—isoniazid, 5 mg/kg per day; rifampin, 10 mg/kg per day; ethambutol, 5 to 25 mg/kg per day; pyrazinamide, 15 to 30 mg/kg per day—and should Table 22-2 Prophylaxis against Tuberculosis in Adults

PPD 5 mm

10 mm

15 mm

Prophylaxis Indicated Regardless of Age Close contacts recently diagnosed with TB HIV positive or HIV risk factors Fibrotic changes on chest radiograph Diabetes mellitus Immunosuppression Hematologic malignancy Injection drug use Renal failure Malnutrition PPD increased >15 mm within 2 yr

Prophylaxis Indicated if 10 mm within 2 yr Native of highprevalence country High-risk ethnic minorities Residents and staff of long-term care facilities No risk factors

HIV, human immunodeficiency virus; PPD, purified protein derivative of tuberculin; TB, tuberculosis.

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be considered before a formal diagnosis is made. Factors suggesting active disease include exposure to active TB, pulmonary symptoms, and cavitary disease on imaging studies. If the diagnosis of TB is confirmed, the drugs are continued for 2 months, barring adverse reactions to drug therapy. After 2 months, the regimen can be tailored, depending on drug-sensitivity studies, and continued for another 4 months with at least two active drugs. Rates of drug-resistant TB are increased in certain populations (e.g., recent immigrants from high TB areas, homeless people). Resistance is detected in 9% of patients who have not received previous therapy and in 22.8% of those with prior treatment. In patients with drug-resistant TB, treatment should include at least three drugs that have not been administered before and to which the organism is susceptible in vitro. Treatment should continue for at least 18 to 24 months. Direct observation of therapy is recommended to ensure compliance.

Pneumocystis Pneumonia Pneumocystis jiroveci, formerly called pneumocystis carinii (PCP), is an opportunistic fungus that occurred mainly in malnourished premature infants and in adults with hematologic malignancy undergoing chemotherapy in the pre– acquired immunodeficiency syndrome (AIDS) era. However, its incidence rose significantly in the late 1980s and 1990s in patients with AIDS with low CD4+ lymphocyte counts (30 breaths per minute), mental deterioration (e.g., impaired judgment, confusion, hallucinations, somnolence), or hemodynamic instability (e.g., bradydysrhythmias or tachydysrhythmias, hypotension) usually require intubation and mechanical ventilation. In the latter circumstances, waiting for arterial blood gas determinations is not necessary and could dangerously delay therapy. Although arterial blood gas evaluation is crucial when determining the need for mechanical ventilation in the patient with respiratory failure, the patient’s clinical status will ultimately dictate the course of action.

Mechanical Ventilation Mechanical ventilation primarily uses the principals of positive pressure ventilation. Air is forced into the central airways, increasing central airway pressure. Air follows the pressure gradient from the central airways to the alveoli, which inflates the lungs. As the lungs inflate and the device stops forcing air into the central airways, the intra-alveolar pressure increases and central airway pressure decreases. Exhalation occurs when the air follows the newly reversed pressure gradient from the alveoli to the central airways. The principal benefits of mechanical ventilation during respiratory failure are improved gas exchange and decreased work of breathing. Mechanical ventilation improves gas 259

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Q) exchange by improving ventilation-perfusion ratio ( V matching. The improved V Q matching is primarily a consequence of decreased physiologic shunting. Altered lung mechanics (e.g., increased airways resistance, decreased compliance) and increased respiratory demand (e.g., metabolic acidosis) increase the work of breathing. The ventilatory muscles and diaphragm can tire while trying to maintain the elevated work of breathing, resulting in respiratory failure. Mechanical ventilation can assume some or all of the increased work of breathing, allowing the ventilatory muscles to recover from their fatigue. Deteriorating gas exchange, unresponsive to conservative measures, and respiratory distress are the most common reasons for mechanical ventilation in patients with acute respiratory failure.

NONINVASIVE MECHANICAL VENTILATION Although intubation and mechanical ventilation are usually the preferred options in respiratory failure that is considered reversible, noninvasive positive-pressure ventilation (NPPV) has proved useful in selected patients. NPPV refers to positive-pressure ventilation delivered through a noninvasive interface (nasal mask, facemask, or nasal plugs), rather than an invasive interface (endotracheal tube, tracheostomy). Its use has become more common as benefits are increasingly recognized. Selecting patients for NPPV requires careful consideration of its indications and contraindications. Generally speaking, a trial of NPPV is worthwhile in patients with acute cardiogenic pulmonary edema or hypercapnic respiratory failure due to COPD who do not require emergent intubation and do not have contraindications to NPPV. Contraindications to NPPV include cardiac or respiratory arrest; inability to cooperate, protect the airway, or clear secretions; severely impaired consciousness; facial surgery, trauma, or deformity; anticipated prolonged duration of mechanical ventilation; and recent esophageal anastomosis.

INVASIVE MECHANICAL VENTILATION Once a decision to intubate is made, an experienced operator should expeditiously perform intubation. Complications of intubation are usually related to prolonged hypoxemia as a result of delays in the procedure, but they also include vomiting and aspiration of gastric contents, trauma to the vocal cords, bleeding, pneumothorax, cardiac arrhythmias, and cardiac arrest. Once inserted, the endotracheal tube should be secured and its position assessed by examining for breath sounds, followed by chest radiography for confirmation. Direct visualization through a bronchoscope is occasionally needed for successful intubation. A ventilator should be available before the procedure is begun so that mechanical ventilation can start as soon as the endotracheal tube is secured. Initial ventilator settings may vary, but typically they include a ventilator mode, fraction of inspired oxygen (Fio2) of 1 (or 100%), respiratory rate set at 10 to 12 breaths per minute, and tidal volume of 400 to 600 mL. The adequacy of the ventilator settings needs to be determined with repeated arterial blood gas levels and the clinical evaluation of the patient. Persistent cyanosis, pallor, diaphoresis, and restlessness may suggest that the tube is misplaced or that

the ventilator settings are insufficient to ventilate the patient appropriately. Positive end-expiratory pressure (PEEP) might be required in patients with refractory hypoxemia. PEEP prevents the premature collapse of the alveoli during matching, leading to improved Q expiration and improves V oxygenation. Once the settings are adjusted to maintain relatively normal levels of arterial blood gases (pH, 7.3 to 7.45; Pao2 > 60 mm Hg; Pco2, 30 to 45 mm Hg), attention should be given to developing a maintenance plan that will secure adequate oxygenation and ventilation until the cause of the respiratory failure is treated and the failure is reversed. This plan should include assessment of the need for sedation, appropriate strategy of mechanical ventilation, supportive measures to achieve hemodynamic stability, nutritional assessment, and therapies targeting the initial injurious process that triggered the respiratory failure (e.g., pneumonia, pulmonary embolism, asthma, shock). Most patients require sedation to diminish discomfort and to decrease the work of breathing, but it should be administered carefully because sedation is often accompanied by a decrease in blood pressure. Commonly used modes of ventilation are determined by the duration of inspiration, which can be limited by volume, pressure, flow, or time. During volume-limited ventilation, inspiration ends after delivery of a preset tidal volume. Airway pressure is variable during volume-limited ventilation and is related to respiratory system compliance, airway resistance, and tubing resistance. Assist control (AC), continuous mandatory ventilation (CMV), and synchronized intermittent mandatory ventilation (SIMV) are examples of modes of ventilation that can be volume limited. CMV has a set rate and set tidal volume which does not allow spontaneous breathing by the patient. Patient-ventilator asynchrony is a big problem, and therefore CMV is rarely used. The assist-control mode of ventilation is similar to CMV in that there is a set rate and tidal volume, but this mode allows the patient to initiate additional spontaneous breaths. When the machine senses that the patient is attempting to take a breath, it delivers the selected tidal volume. SIMV is similar to assist-control in that a set rate and tidal volume are selected. The patient is also able to generate a spontaneous breath. However, this spontaneous breath may have a very small tidal volume, yet entail significant work of breathing. Consequently, this mode of mechanical ventilation is seldom used except when weaning patients from mechanical ventilation. The pressure control mode of ventilation uses machine breaths that are pressure cycled, not volume cycled. With pressure control ventilation, the pressure to be used for each breath is ordered. If the patient attempts a spontaneous breath, a machine breath at the designated pressure is delivered. This may be helpful in limiting airway pressures in patients with bronchospasm or stiff lungs because it limits the risk for pneumothorax (barotrauma). Because tidal volumes may vary, the pressure control mode must be titrated carefully at the bedside to determine the proper pressure settings. Pressure support ventilation is used only for spontaneously breathing patients. The inspiratory and expiratory pressures are selected, and there are no mandatory machine breaths. Patients find this to be a more comfortable mode of mechanical ventilation. However, pressure support ventilation

Chapter 23—Essentials in Critical Care Medicine should only be used for patients with a stable respiratory drive (not sedated heavily) and stable lung compliance. Pressure support ventilation is typically used for patients who are weaning from mechanical ventilator support. Pressure-regulated volume control, airway pressure release ventilation, and high-frequency ventilation are newer modalities that are increasingly used in clinical practice.

SETTINGS Numerous settings need to be considered when mechanical ventilation is initiated. These include tidal volume, respiratory rate, trigger mode and sensitivity, fraction of inspired oxygen, PEEP, flow rate, and flow pattern. The appropriate initial tidal volume depends on numerous factors, most notably the disease for which the patient requires mechanical ventilation. The tidal volume can then be increased or decreased incrementally to achieve the desired pH and arterial carbon dioxide tension (Paco2). Generally speaking, large tidal volumes can cause barotrauma or volutrauma, which increases the risk for ventilator-associated lung injury. Therefore, tidal volume should not be increased without considering effects on airway pressure or the likelihood of ventilator-induced lung injury. An optimal method for setting the respiratory rate has not been established. Once the tidal volume has been established, the respiratory rate can be incrementally increased or decreased to achieve the desired pH and Paco2, while monitoring auto-PEEP. Patients who are breathing spontaneously will set their own respiratory rates in all modes of ventilation except CMV. The lowest possible fraction of inspired oxygen (FiO2) necessary to meet oxygenation goals should be used. This will decrease the likelihood that adverse consequences of supplemental oxygen will develop, such as absorption atelectasis, accentuation of hypercapnia, airway injury, and parenchymal lung injury. PEEP is generally added to prevent end-expiratory alveo matching and Q lar collapse. This generally improves V arterial oxygenation and allows reduction in Fio2, thereby reducing the risk for oxygen toxicity. However, elevated levels of applied PEEP can have adverse consequences, such as reduced preload (decreases cardiac output), elevated plateau airway pressure (increases risk for barotrauma), and impaired cerebral venous outflow (increases intracranial pressure). The optimal PEEP is that which enhances oxygenation without lung hyperinflation and decreased blood pressure. Respiratory therapists typically also adjust the inspiratory flow rate, flow pattern, and amount of negative pressure required to “trigger” a mechanical ventilator breath. If these ventilator settings are not adjusted with due consideration of the patient’s respiratory mechanics, two common problems can occur: asynchrony and auto-PEEP. Patientventilator asynchrony occurs if the phases of breaths delivered by the ventilator do not match the breathing pattern of the patient. Patient-ventilator asynchrony can cause dyspnea, increase the work of breathing, and prolong the duration of mechanical ventilation. It is detected by careful observation of the patient and examination of the ventilator waveforms. Generally, the abnormality that is most readily apparent is

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failure of the ventilator to trigger a breath when the patient makes an inspiratory effort. Auto-PEEP is usually seen when patients are not fully emptying their lungs during expiration before the initiation of the next breath. This is known as stacking breaths or generating auto-PEEP. This is particularly worrisome in patients who have exacerbations of COPD or status asthmaticus requiring mechanical ventilation. In ventilated patients, auto-PEEP may cause barotrauma or hemodynamic collapse owing to high intrathoracic pressures preventing blood return to the right ventricle.

Weaning from Mechanical Ventilation The complications of endotracheal intubation and mechanical ventilation are many; trauma to the lung from high ventilator pressures (barotrauma), volutrauma and ventilator-induced lung injury, and pneumonia are the most significant. Therefore, the patient who is mechanically ventilated must be treated aggressively and monitored carefully. Weaning from mechanical ventilation should be considered when the original insult that caused respiratory failure has cleared, especially if the patient is awake and cooperative and shows no signs of respiratory or hemodynamic instability. Weaning is usually not attempted if requirements for oxygen supplementation remain high (Fio2 > 0.5). Conventional parameters that determine whether weaning is possible include negative inspiratory force, vital capacity, tidal volume, respiratory rate, and minute ventilation (Table 23-1). Unfortunately, the strength of these parameters lies in the ability to predict failure to wean rather than in the ability to predict successful spontaneous breathing. A better way to assess weaning capability is to engage the patient in a short weaning trial during which support from the ventilator is diminished. This trial can be achieved by allowing the patient to breathe oxygen for 1 hour without providing supporting pressure. Another strategy is to decrease the pressure generated by the ventilator during a trial of continuous positive airway pressure (CPAP). The patient is monitored for any signs of distress or hemodynamic instability, and arterial blood gas levels are measured to determine the effectiveness of spontaneous ventilation. If the patient tolerates the trial, extubation may be indicated, depending on the patient’s clinical status and his or her underlying condition. In general, Table 23-1 Conventional Weaning Parameters Parameters NIF (cm of water) VC (mL/kg) VT (mL/kg) RR (breaths/min) VE (L/min) Rapid shallow breathing index (RSBI) (RR/VT)

Weanable Values

Normal Ranges

10 10 3 cm diameter or tumor of any size with any of the following characteristics: Invasion of visceral pleura Atelectasis of less than entire lung Proximal extent at least 2 cm from carina T3—Tumor of any size with any of the following characteristics: Invasion of chest wall Involvement of diaphragm, mediastinal pleura, or pericardium Atelectasis involving entire lung Proximal extent within 2 cm of carina T4—Tumor of any size with any of the following: Invasion of mediastinum Invasion of heart or great vessels Invasion of trachea or esophagus Invasion of vertebral body or carina Presence of malignant pleural or pericardial effusion Satellite tumor nodule(s) within same lobe as primary tumor Nodal Involvement (N) N0—No regional node involvement N1—Metastasis to ipsilateral hilar and/or ipsilateral peribronchial nodes N2—Metastasis to ipsilateral mediastinal and/or subcarinal nodes N3—Metastasis to contralateral mediastinal or hilar nodes or ipsilateral or contralateral scalene or supraclavicular nodes Metastasis (M) M0—Distant metastasis absent M1—Distant metastasis present (includes metastatic tumor nodules in a different lobe from the primary tumor) Stage Groupings of TNM Subsets Stage Stage Stage Stage

IA IB IIA IIB

T1 T2 T1 T2 T3

N0 N0 N1 N1 N0

M0 M0 M0 M0 M0

Stage IIIA Stage IIIB Stage IV

T3 N1 M0 T1-3 N2 M0 Any T N3 M0 T4 Any N M0 Any T Any N M1

Adapted from Greene FL, Page DL, Fleming ID: AJCC Cancer Staging Manual, 6th ed. New York, Springer, 2002.

disease is limited. Combinations of cisplatin and etoposide are the standard chemotherapeutic regimen. Although chemotherapy and radiation often produce a dramatic response and sometimes are curative for limited disease, relapse is typical, and subsequent treatments are less effective. Prophylactic cranial radiation may be performed. Surgery is the only curative therapy for NSCLC and is indicated for patients with stage I or II NSCLC who are operative candidates. Lobectomy (or greater) extent of resection is considered superior to more limited resection such as a wedge resection. Adjuvant chemotherapy is appropriate for patients with stage II disease. For patients with stage IIIA lung cancer, the optimal treatment strategy remains unclear, in part because of the heterogeneity of patients in this group. In general, these patients are not candidates for surgery alone, if at all, and a treatment plan should be developed for each patient in a multidisciplinary setting. In stage IIIB,

269

surgery may rarely be indicated for some T4 N0-1 M0 tumors. However, most patients with stage IIIB NSCLC are not surgical candidates, and 5-year survival is poor for this group. Combined, ideally concurrent, chemotherapy and radiotherapy are preferable to radiotherapy alone in patients with stage IIIB NSCLC. In stage IV, chemotherapy is recommended because it improves survival and provides palliation for symptoms. Targeted molecular therapies are an area of active interest in lung cancer treatment. Highlighting the challenges of these new targeted therapies, bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, was associated with hemoptysis, which was sometimes fatal, in patients with squamous cell carcinoma in an early-stage trial. However, bevacizumab improved survival when added to a standard platinum-based chemotherapeutic regimen in patients with nonsquamous NSCLC. Erlotinib, a tyrosine kinase inhibitor targeting the activity of the epidermal growth factor receptor, is approved for the second-line treatment of metastatic NSCLC. Targeting the epidermal growth factor receptor appears to have benefit in particular patient groups, such as women, never-smokers, and Asians, harboring particular receptor mutations.

Special Circumstances SOLITARY PULMONARY NODULE A solitary pulmonary nodule (SPN) is a single, rounded lesion in the lung that is 3 cm or less in diameter. Although these lesions are commonly lung cancers in certain patient populations, the differential diagnosis of this radiographic finding is broad and includes many malignant and benign etiologies. In addition to primary lung cancer (with adenocarcinoma the most common type to present as an SPN (see Web Fig. 24-12), other malignant etiologies include bronchial carcinoid tumors and metastatic foci from extrapulmonary malignancies (most common sources include malignant melanoma, sarcoma, colon, kidney, breast, and testicle). Benign etiologies include benign tumors of the lung (hamartomas (Web Fig. 24-14), infectious granulomas (from fungal diseases including histoplasmosis and coccidioidomycosis as well as mycobacterial disease), lung abscess, vascular abnormalities (arteriovenous malformation), rounded atelectasis, and pseudotumor (pleural fluid trapped within a fissure). When confronted with a patient with a solitary pulmonary nodule, determining the likelihood of malignancy is critically important because early resection of malignant nodules is usually curative, whereas resection of benign nodules exposes the patient to an unnecessary risk for surgery. Diagnostic evaluation includes consideration of certain clinical features, including patient age and risk factors. The probability of an SPN being malignant increases with patient age. However, even in younger individuals (7 METs) Carry 24 lb up eight steps Carry objects that weigh 80 lb Outdoor work (shovel snow, spade soil) Recreation (ski, basketball, squash, handball, jog or walk 5 mph)

• Emergent major operations, especially in elderly patients • Aortic and other major vascular (endovascular and nonendovascular) surgery • Noncarotid peripheral vascular surgery • Prolonged surgery associated with large fluid shift and/or blood loss

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Intermediate Risk

Moderate (activities requiring >4 but 70, 3.5 g/1.73 m2 per day), edema, and hypoalbuminuria Oval fat bodies, coarse granular casts

Poststreptococcal glomerulonephritis

Nephrotic syndrome With bland urine sediment (pure nephrotic) Asymptomatic urinary abnormalities Tubulointerstitial nephropathy Acute renal failure Rapidly progressive renal failure Tubular defects

Isolated proteinuria (36 to 48 hours), the brain generates compounds that raise the intracellular osmolality and thereby minimize cell shrinkage. This process is metabolically driven and is slow to return to normal. Thus, rapid correction of plasma osmolality may lead to a shift of water to the relatively hypertonic intracellular compartment and may result in brain edema. As a general rule, hypernatremia should be corrected over 48 hours at a rate not exceeding 0.5 mEq/L per hour, or 12 mEq/L per day.

Disturbances in Potassium Balance The human body contains about 3500 mEq of potassium. With a normal concentration of 3.5 to 5 mEq/L, the ECF contains about 70 mEq of potassium, or only 2% of totalbody stores. In response to a dietary potassium load, rapid removal of potassium from the extracellular space is necessary to prevent life-threatening hyperkalemia. For example, in the absence of a homeostatic mechanism, if a person ingests 50 mEq of dietary potassium in a single meal (the average daily American diet contains 100 to 120 mEq of potassium per day), the serum potassium might rise to 7 mEq/L (assuming an extracellular volume of 14 L with a baseline serum potassium of 4 mEq/L). Thus, the initial adaptation to a potassium load is the rapid redistribution of potassium from the extracellular space to the intracellular space. Various hormones, including insulin, aldosterone, and catecholamines, cause movement of potassium into cells. The acid-base status of the patient is another determinant of the serum potassium concentration because potassium moves across cell membranes driven by pH gradients between the cell and the ECF compartments. The greatest effect on the serum potassium concentration is associated with metabolic acidosis involving mineral acids. The cellular permeability to the anions of the mineral acids is low; consequently, the basolateral membrane is hyperpolarized, provoking potassium movement into the blood. By contrast, metabolic acidosis caused by organic acids, such as lactic acid and keto acids, does not cause hyperkalemia. The anions of these acids are relatively permeable and accompany hydrogen into the cell. This situation diminishes the electrochemical gradient favoring potassium efflux.

Although these mechanisms affect the distribution of potassium between the fluid compartments, other mechanisms are necessary to maintain overall potassium balance. People ingest about 100 mEq of potassium daily, the bulk of which is eliminated by the kidneys. Increased potassium excretion results from enhanced distal nephron potassium secretion by the principal cells of the connecting tubule and collecting duct into the tubular lumen down an electrochemical gradient. Factors that enhance this gradient promote potassium secretion. These factors include the rate of distal tubular flow, the distal delivery of sodium, the presence of poorly reabsorbable anions in the tubular fluid, and stimulation by aldosterone. The ratio of extracellular to intracellular potassium establishes the resting membrane potential of the cell. Hence hyperkalemia or hypokalemia is associated with alteration of the resting membrane potential, which accounts for most of the symptoms and findings in these disorders.

DIAGNOSTIC APPROACH A careful history with emphasis on the patient’s diet and use of medications and laxatives should be obtained. Spurious hyperkalemia and hypokalemia must be excluded. In addition to serum electrolytes and magnesium, urine electrolytes and urine osmolality should be obtained. The next step should be to determine whether abnormal renal potassium handling is involved in the genesis of the disorder. This state may be determined by measuring the 24-hour urine potassium excretion. In extrarenal hyperkalemia, renal potassium excretion should be more than 200 mEq/day, and if hypokalemia is caused by extrarenal losses, the renal potassium excretion should be less than 20 mEq/day.

HYPERKALEMIA The ratio of intracellular to extracellular potassium concentration is the major determinant of the resting potential of the cell membrane. As the extracellular potassium concentration increases, the cell membrane is partially depolarized, the sodium permeability is diminished, and the ability to generate action potentials is decreased. In muscle tissue, this change accounts for muscle weakness and paralysis. In the heart, hyperkalemia exhibits as changes in the electrocardiogram. These changes include peaked T waves, decreased amplitude or the absence of P waves, wide QRS complexes, sinus bradycardia, and conduction defects. A pathophysiologic approach to the causes of hyperkalemia is outlined in Figure 28-6. Vigorous phlebotomy techniques can result in lysis of red blood cells, a process that releases intracellular potassium into the serum sample. Thrombocytosis (>1 × 106/µL) and leukocytosis (>60,000/µL) may also be associated with spurious hyperkalemia. These disorders can be diagnosed rapidly by determining the plasma and serum concentrations of potassium. True hyperkalemia is present if these values differ by less than or equal to 0.2 mEq/L. Chronic renal insufficiency does not cause hyperkalemia unless it is advanced, with a GFR ranging from less than 10 to 15 mL per minute. Thus, hyperkalemia in chronic renal insufficiency is usually caused by a distal nephron defect in potassium secretion rather than by the impaired GFR, as

Chapter 28—Fluid and Electrolyte Disorders

313

Hyperkalemia

Pseudohyperkalemia • Hemolysis • Thrombocytosis • Leukocytosis

Redistribution • Acidosis • ↓Insulin • β-Adrenergic blockade • Arginine infusion • Succinylcholine • Digitalis overdose (massive) • Periodic paralysis

Impaired renal K+ excretion* (TTKG 60,000 cells/µL), resulting from active uptake of potassium by white blood cells from the serum. True hypokalemia is caused by redistribution, extrarenal potassium loss, poor intake, or renal potassium losses. Because only 2% of total-body potassium is distributed in the extracellular compartment, serum potassium measurements may not accurately reflect the total-body stores. In fact, hypokalemia can occur in the presence of normal total-body potassium stores. This state occurs when potassium shifts from the extracellular space to the intracellular space. Excess circulating catecholamines, insulin administration, and alkalosis are the major causes of redistribution of potassium from the extracellular space to the intracellular space. Redistribution hypokalemia is particularly important in the clinical setting of myocardial infarction and exacerbation of chronic obstructive pulmonary disease. These patients are especially prone to arrhythmias because excess catecholamines (in response to stress or

314

Section VI—Renal Disease Hypokalemia

Normal acid-base

Redistribution • Catecholamine excess • Alkalosis • Hypokalemic periodic paralysis • Insulin administration • Barium poisoning

Extrarenal losses • Decreased intake (e.g., anorexia nervosa) • Laxative abuse

Metabolic acidosis

Extrarenal losses (urine K+ 2) • Renal tubular acidosis • Organic acidosis (lactic and ketoacidosis) • Carbonic anhydrase inhibitors

Urine K+ 20 mEq/L

High blood pressure • Hyperaldosteronism • Essential hypertension with diuretic use • Hypercortisolism • Apparent mineralocorticoid excess (licorice ingestion, Liddle syndrome)

Figure 28-7 Diagnostic approach to hypokalemia. TTKG, transtubular potassium gradient.

inhaled β2 agonists) cause potassium shifts in the setting of total-body potassium depletion from frequent diuretic usage. In patients with hypokalemia, the acid-base status, the presence or absence of hypertension, and measurement of urinary chloride and potassium are helpful in narrowing the diagnostic possibilities. In patients with diuretic abuse (usually patients with eating disorders), the urine sodium and chloride concentrations are high in the presence of metabolic alkalosis, a profile similar to that of Bartter syndrome, which is a rare genetic defect usually seen in adolescents with other neurologic abnormalities and caused by reduced activity of the sodium, potassium, and chloride (NKCC2) co-transporters in the thick ascending limb (see later). In this setting, a urine screen for diuretics may be necessary to make the diagnosis. In comparison, patients with surreptitious vomiting have a low urinary chloride concentration. Patients who abuse laxatives have low urine sodium and chloride concentrations, with metabolic acidosis or normal acid-base status. Glycyrrhizic acid, the active ingredient in licorice, blocks 11β-dehydrogenase, an enzyme that inactivates glucocorticoids, and its inhibition results in unregulated activation of the mineralocorticoid receptors in the distal nephron. Determination of serum magnesium should always be performed in a patient with hypokalemia. Hypokalemia that is associated with hypomagnesemia is resistant to therapy unless concomitant magnesium deficiency is corrected. Given the factors that determine transmembrane potassium shifts, the net potassium deficit may be difficult to

calculate. An estimate for a 70-kg man based on the serum concentration is a 100- to 200-mEq deficit in total-body potassium when the serum concentration decreases from 4 to 3 mEq/L. At less than 3 mEq/L, every 1-mEq/L decrease in the serum concentration of potassium reflects an additional 200- to 400-mEq deficit in total-body potassium. Hypokalemia should be treated with oral potassium supplementation. Intravenous potassium administration should only be used in urgent situations, such as in patients with arrhythmias or digitalis toxicity, and intolerance to oral formulations in patients with adynamic ileus. The rate of intravenous potassium administration generally should not exceed 10 mEq per hour; only under electrocardiographic monitoring, the potassium administration rate can be increased up to 20 mEq per hour. Hypokalemia associated with long-term diuretic therapy may be treated with the addition of a potassium-sparing diuretic.

Bartter and Gitelman Syndromes A major advance in the study of inherited disorders of salt-wasting syndromes has been the demonstration that Bartter and Gitelman syndromes result from mutation of specific ion transport proteins expressed by cells of the distal nephron. The dysfunction of the thiazide-sensitive sodiumchloride co-transporter (NCCT) in Gitelman syndrome, and the bumetanide-sensitive sodium-potassium-chloride


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Table 28-6 Various Bartter Syndromes Gene name Protein name Major symptoms Seizures Urine Ca2+ Urine Mg2+ Nephrocalcinosis

Type 1

Type 2

Type 3

Type 4

Type 5

SLC12A1 NKCC2 Polyuria, hypocalcemia Dehydration ↑ ↓ +++

KCNJ1 ROMK As for type 1 — ↑ ↓ +++

CLCNKB CLCNKB Variable Mild to severe ↑ ↓ ±

BSND Barttin As for type 1 + Deafness ↑ ↓ −

CASR CaR — — ↑ ↓ +++

Ca2+, calcium; Mg2+, magnesium.

Table 28-7 Known Pathophysiology of Gitelman Syndrome Loss of functional mutation: NCCT NaCl wasting Secondary hyperaldosteronism: K wasting Cellular hyperpolarization secondary decreased Cl− entry ↑ Apical ECaC entry ↑ Basolateral Na/Ca exchange Net effect: hypocalciuria Mg wasting: uncertain mechanism

(NKCC2) co-transporter in Bartter syndrome cause salt wasting, extracellular volume depletion, secondary hyperaldosteronism, and hypokalemia. The various characteristics of the five different Bartter syndromes and the Gitelman syndromes are shown in Tables 28-6 and 28-7. Stated briefly, Bartter syndrome is a genetically heterogeneous disease. Based on molecular genetic studies, five different subtypes of Bartter syndromes can be distinguished. Type I, or neonatal Bartter syndrome, is caused by loss of function mutations in the sodium-potassium-chloride co-transporter NKCC2. NKCC2 is encoded by the SCL12A1 gene on chromosome 15. This sodiumpotassium-chloride co-transporter is expressed in the apical cell membranes of the thick ascending limb of the loop of Henle (TAL), and normally accounts for about 30% of total reabsorption of sodium filtered by the glomerulus. Patients with this syndrome present early in life with a severe systemic disorder characterized by marked sodium and potassium wasting, polyhydramnios, and significant hypercalciuria and nephrocalcinosis. Prostaglandin synthesis and excretion are significantly increased and may account for much of the systemic symptoms. Bartter syndrome type II is due to loss of function mutation of the KCNJ1 gene on chromosome 11, encoding the inward rectifier voltage-dependent potassium channel ROMK. The potassium channel ROMK is localized in the apical membrane of TAL but is also expressed in the cortical collecting duct. In the TAL, the potassium flow through this channel into the renal tubule is necessary for NKCC2 activity, which needs adequate luminal potassium supply. In the cortical collecting duct, this channel is also involved in the excretion of dietary potassium. In this syndrome, an aberrant ROMK channel leads to malfunction of the NKCC2 co-transporter and results in salt wasting, high tubular flow, and distal potassium wasting. Bartter syndrome type III is

caused by loss of function mutations of the CLCNKB gene on chromosome 1 encoding a chloride channel protein CLC-Kb. This protein is expressed in the basolateral cell membranes of the TAL and is responsible for the reabsorption of sodium chloride in the TAL. The renal salt wasting in Bartter type III syndrome is less severe than types I and II. Recently, Bartter syndrome type IV was found to be caused by loss of function mutation of the BSND gene (Bartter syndrome and sensorineural deafness) on chromosome 1p31. The BSND gene encodes barttin, a protein expressed in the basolateral membrane of the TAL. Barttin is the β subunit of the ClC-Kb chloride channel; it is necessary for ClCKb delivery to the plasma membrane; and in the cochlea, it co-localizes with chloride channels ClCKa and ClCKb. These patients present also with sodium, potassium wasting, and impaired cochlear function and deafness. Recently, the presence of hypokalemic alkalosis due to Bartter syndrome type V was found in patients with autosomal dominant hypocalcemia. In this disease, hypocalcemia was related to gain of function mutation of the calcium-sensing receptor (CaSR). The CaSR is heavily expressed at the basolateral membrane of the TAL, where it is thought to play an important inhibitory role in regulating the transcellular transport of sodium, chloride, and calcium. Activation of the basolateral CaSR in the TAL reduces apical K+ channel activity, which induces a Bartter-like syndrome. Genetic activation of the CaSR by these mutations is also expected to increase urinary calcium excretion by inhibiting the generation of the lumen positive potential difference that drives paracellular calcium transport in the TAL. To date, Gitelman syndrome appears to be molecularly homogeneous. Although a loss of function mutation of the SLC12A3 gene in chromosome 16q13 has been identified as one of the causes, recent genetic characterization of Gordon syndrome, a disease with clinical features opposite to Gitelman syndrome, suggests the possibility that similar mirror-image mutations and possibly more than one, might account for Gitelman syndrome. The SLC12A3 gene encodes the renal thiazide-sensitive sodium-chloride co-transporter NCCT. NCCT is responsible for the sodium reabsorption in the distal tubule, which accounts for about 7% of the total filtered sodium. Although Gitelman syndrome is a milder disorder than Bartter syndrome, patients do report significant morbidity related to muscular symptoms, fatigue, and increased risk for cardiac arrhythmias in patients having a prolonged QT interval. Although plasma renin activity is increased, renal prostaglandin excretion is not elevated, another feature that distinguishes Gitelman syndrome from Bartter syndrome.

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A major phenotypic difference between Bartter and Gitelman syndromes involves urinary calcium excretion. The hypercalciuria of Bartter syndrome is believed to result largely from dysfunction of thick ascending limb cells. Calcium absorption, which is passive and paracellular, is driven by lumen-positive transepithelial voltage that is generated by NKCC2 co-transport and luminal K+ recycling. When NKCC2 co-transport is reduced or blocked by loop diuretics or genetic abnormality, the lumen positivity declines, and calcium reabsorption declines. What is not entirely clear is why the loss of luminal positivity does not lead to increased magnesium excretion. In addition to this mechanism, increased distal delivery of NaCl, as a result of dysfunction of the TAL raises intracellular chloride concentration, which in turns inhibits apical calcium channel of distal convoluted tubule (DCT) cells, further contributing to calcium retention and nephrolithiasis. In contrast to patients with Bartter syndrome, patients with Gitelman syndrome invariably demonstrate hypocalciuria. The hypocalciuria of Gitelman syndrome resembles the clinical beneficial effects of DCT diuretics (thiazides and others) to reduce urinary calcium excretion. The mechanisms of hypocalciuria in Gitelman syndrome are well established. First, mild contraction of the ECF volume increases calcium reabsorption along the proximal tubule. Second, reduction in NaCl entry to DCT cells stimulates transepithelial calcium transport. When apical Na and Cl entry into DCT cells is inhibited, because of either diuretic treatment or genetic disease, the intracellular chloride concentration declines. Lower intracellular Cl activity hyperpolarizes the cell and activates calcium entry through the distinctive apical calcium channels ECaC and CaT2, expressed in the DCT cells. Because calcium movement from lumen to cell must be balanced, the increased calcium entry to DCT cells stimulates calcium efflux through the basolateral Na+/Ca+ exchanger and the Ca-ATPase. Therefore, the resultant effect is the development of hypocalciuria. Although the pathogenesis of calcium disorders in Bartter and Gitelman syndromes is relatively clear, only recently has the pathogenesis of magnesium disorders associated with these syndromes been clarified. Gitelman syndrome is associated with severe hypomagnesemia, whereas Bartter syndrome is not. Recent observations in genetic disorders of hypomagnesemia, as well as clinical observations in patients undergoing chemotherapy with anti–epidermal growth factor (EGF) antibodies have helped to clarify the molecular mechanisms involved in magnesium transport. Magnesium is absorbed along the entire nephron, but the predominant site for reabsorption is along the distal tubule. In the medullary and cortical TAL, magnesium, along with calcium, is reabsorbed through a charge-selective paracellular path. Mutations in claudin-16 (also called paracellin) and claudin19 cause severe hypomagnesemia and nephrocalcinosis. In the DCT, a specific channel, the transient receptor potential melastatin, subfamily 6 channel, TRPM6, mediates magnesium reabsorption. Mutations in the EGF gene, which is expressed in the distal tubule, cause hypomagnesemia, and anti-EGF antibodies induce hypomagnesemia. The latter observations suggest a regulatory role of EGF in the reabsorption of magnesium. Knockout of the thiazide-sensitive sodium chloride co-transporter and inhibition of this transporter with thiazides cause hypomagnesemia and reduce

TRPM6 expression. Thus, reduced expression of the TRPM6 channel is the most likely explanation of the hypomagnesemia seen in Gitelman syndrome.

Disturbances in Acid-Base Balance Most metabolic processes occurring in the body result in the production of acid. The largest source of endogenous acid production is from the complete catabolism and oxidation of glucose and fatty acids ultimately to carbon dioxide and water. Pulmonary ventilation excretes the volatile acid produced by such cellular respiration, about 22,000 mEq of hydrogen daily, as carbon dioxide. Cellular metabolism of sulfur-containing amino acids, the oxidation of phosphoproteins and phospholipids, nucleoprotein degradation, and the incomplete combustion of carbohydrates and fatty acids result in the formation of nonvolatile acids. These processes produce about 1 mEq/kg body weight of hydrogen daily. Nonvolatile acid excretion is effected through the kidney. The primary factors regulating alteration in the rate of minute ventilation are changes in cerebrospinal fluid and arterial blood pH. The normal concentration of hydrogen in arterial blood is 40 mEq/L, equal to a pH of 7.40. This concentration is maintained relatively constant despite variations in the endogenous and exogenous acid inputs. Circulating and intracellular buffers acutely neutralize an acid load. The capacity of these buffering systems is limited, however, and would be quickly depleted by normal endogenous acid production. Mechanisms for excreting acid must therefore be effective to regenerate these buffers to maintain acid-base homeostasis.

RENAL HYDROGEN ION EXCRETION The kidney contributes to acid-base homeostasis by the reclamation of 4500mEq of bicarbonate filtered at the glomerulus daily and by the generation of new bicarbonate. This renal bicarbonate generation is given by the equation for net acid excretion (NAE): E NAE = ENH4+ + E TA − EHCO3− where ENH4+ + ETA is the rate of ammonium and titratable acid excretion, respectively, and EHCO3−1 is the rate of bicarbonate excretion. Although not difficult, measurement of NAE is not routinely done, and thus analysis of acid-base disorders has relied on indirect but more readily available measurements. The principal process of renal bicarbonate generation is accomplished by urinary acidification and ammonia generation. Ammonia is generated from glutamine and secreted into the tubule fluid by the proximal tubule epithelium. Acidification is accomplished by proton secretion by distinct transporters uniquely distributed along the nephron. These transporters were highlighted in Chapter 26, and this chapter discusses how they modify the tubular fluid pH. The acidification profile of tubular fluid is shown in Figure 28-8. Tubule fluid pH falls slightly along the proximal tubule by


Table 28-8 Systemic Approach to the Analysis of Acid-Base Disorders

% Proximal tubule

0.2 0 0.2

% Distal Ureteral convolution urine + 0 20 40 60 80 100 0 50 100 ∆pH ∆pH − −

0 0.2

0.4

0.4

0.6

0.6

0.8

0.8

1.0

1.0 1.2 9 Nondiuretic rats

317

1.4 1.6 1.8 2.0

Figure 28-8 pH changes along the rat nephron.

the operation of the sodium-hydrogen exchanger type 3 (NHE3) located at the luminal membrane. This proton secretion is linked to bicarbonate reabsorption, and nearly 90% of the filtered load of bicarbonate is reabsorbed from the tubule fluid during its course along the proximal tubule. The proximal tubule is a high-capacity bicarbonate reabsorption system whose rate results from the presence of carbonic anhydrase in the luminal membrane. Carbonic anhydrase in the luminal membrane rapidly catalyzes the dehydration of carbonic acid to carbon dioxide and water and thus restricts the fall in tubule fluid pH along the proximal tubule and prevents the development of too steep a pH gradient into which sodium-hydrogen exchange takes place. The distal tubule, on the other hand, lacks a luminal carbonic anhydrase and has a limited capacity to reabsorb bicarbonate. However, given that the bicarbonate concentration reaching these sites is low and the principal buffers in the tubule fluid along these sites are ammonia and phosphate ions, the continued operation of the distal proton pumps lowers the prevailing urinary pH to sometimes 1000fold below the pH of the initial filtrate. Along these sites, however, the full operation of the kidney in acid-base homeostasis is observed as the urinary buffers are titrated by secreted protons from pumps distributed along the distal nephron and excreted into the urine. The rate of bicarbonate generation is not fixed and responds to changes in volume and electrolyte status, hormones, and acid-base parameters. Proximal bicarbonate reabsorption is increased during volume depletion, by elevation in the partial pressure of carbon dioxide (Pco2), as seen in chronic respiratory acidosis, and by hypokalemia. Conversely, volume expansion or the reduction of the Pco2 lowers the proximal tubular reabsorptive rate for bicarbonate. Aldosterone and ambient Pco2 affect the rate of distal nephron hydrogen ion secretion.

ASSESSMENT OF ACID-BASE STATUS A systematic approach to assessing acid-base status consists of several steps, as summarized in Table 28-8. The initial step

Assess the accuracy of the acid-base parameters using the Henderson equation (H+ = 24 × [ PaCO2 HCO3− ) or the Henderson-Hasselbalch equation (pH = 6.1 + log[HCO3− 0.03] × Paco2). Obtain a good history and perform a complete physical examination, looking for clues to a particular acid-base disturbance. Calculate the serum anion gap: Na+− ( HCO3− + Cl−). Identify the primary acid-base disturbance and assess whether a simple or mixed acid-base disturbance is present. Examine serum electrolytes and ancillary laboratory data. Measure urine pH and urine electrolytes, urine urea nitrogen, and glucose to calculate the urine anion gap (Na+ + K+− Cl−) or urine osmolal gap (measured osmolality − [2(Na+ + K+) + [urea nitrogen/2.8] + [glucose/18]).* *Measurement of urine Na+ and Cl− and urine pH should be obtained when metabolic alkalosis is present. Measurement of urine electrolytes, urine glucose, and urine pH should be obtained when an element of normal anion gap metabolic acidosis is present.

is to obtain arterial and venous blood samples to measure blood pH and Pco2, as well as serum electrolytes to determine the nature of the acid-base disturbance. Validation of the internal consistency of the calculated and measured bicarbonate should be carried out. Based on the pH, Pco2, and serum bicarbonate, a minimum diagnosis should be established. Next, a measurement of the compensatory response and the anion gap should be performed. If the compensation of a primary acid-base defect is inappropriate, then a mixed acid-base disorder is considered (Table 28-9). The anion gap is useful in the diagnostic approach to metabolic acidosis. When an organic acid, such as lactic acid, is added to the ECF compartment, the bicarbonate concentration falls as the acid is buffered. The anion gap increases as the organic base is accumulated. Quantitatively, the increase in anion gap should be equivalent to the decrease in bicarbonate concentration. Thus, by adding the difference between the calculated and normal anion gap to the prevailing bicarbonate concentration, an estimate of the starting bicarbonate concentration can be made. An abnormally elevated initial bicarbonate concentration indicates concomitant metabolic alkalosis. After establishing the nature of the acid-base disorder and whether it is complex or simple, examination of the urine pH and urine anion or osmolal gap can also provide useful information.

METABOLIC ACIDOSIS Metabolic acidosis is characterized by a decrease in the serum bicarbonate concentration. This decrease occurs either by excretion of bicarbonate-containing fluids or by utilization of bicarbonate as a buffer of acids. In the latter instance, the nature of the base may affect the electrolyte composition. Thus, considering metabolic acidosis by means of the anion gap is convenient (Table 28-10). Metabolic acidoses with a normal anion gap is most commonly caused by extrarenal losses of bicarbonate, as occurs in diarrheal diseases, but may also be caused by abnormally high renal excretion of bicarbonate and by the addition of

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Table 28-9 Nature of Adaptive Response to Primary Acid-Base Disorders Primary Acid-Base Disturbance

Initiating Mechanism

Metabolic acidosis

↓ plasma HCO3−

↓ Paco2 of 1.0-1.3 mm Hg for each 1 mEq/L fall in plasma HCO3− Paco2 = (1.5 × HCO3− ) + 8 + 2

Metabolic alkalosis

↑ Plasma HCO3−

Respiratory acidosis

↑ Paco2

Respiratory alkalosis

↓ Paco2

↑ Paco2 of 0.4 to 0.7 mm Hg for each 1 mEq/L rise in plasma HCO3− Acute: ↑ plasma HCO3− of 1 mEq/L for every 10-mm Hg rise in Paco2 Chronic: ↑ plasma HCO3− of 3.5 mEq/L for every 100-mm Hg fall in Paco2 Acute: ↓ plasma HCO3− of 2 mEq/L for every 10-mm Hg fall in Paco2 Chronic: ↓ plasma HCO3− of 4-5 mEq/L for every 10-mm Hg fall in Paco2

Secondary Physiologic Response

Note: Rare cases with Paco2 values greater than 55 mm Hg have been reported.

Table 28-10 Causes of Metabolic Acidosis Normal Anion Gap Bicarbonate losses Extrarenal Small bowel drainage Diarrhea Renal Proximal renal tubular acidosis Carbonic anhydrase inhibitors Primary hyperparathyroidism Failure of bicarbonate regeneration Distal renal tubular acidosis Aldosterone deficiency Addison disease Hyporeninemic hypoaldosteronism Aldosterone insensitivity Interstitial renal disease Aldosterone antagonists Ureteroileostomy (ileal bladder) Acidifying salts Ammonium chloride Lysine or arginine hydrochloride Diabetes mellitus (recovery phase) Wide Anion Gap Reduced excretion of acids Renal failure Overproduction of acids Ketoacidosis Diabetic Alcoholic Starvation Lactic acidosis Toxin ingestion Methanol Ethylene glycol Salicylates Modified from Andreoli TE: Disorders of fluid volume, electrolyte, and acid-base balance. In Wyngaarden JB, Smith LH Jr, Bennett JC (eds): Cecil Textbook of Medicine, 19th ed. Philadelphia: WB Saunders, 1992, p 523.

substances yielding hydrochloric acid, as when arginine hydrochloride is administered. The urinary anion gap is defined as follows: Urinary anion gap = (sodium + potassium ) − chloride The equation provides an approximate index of urinary ammonium excretion, as measured by a negative urinary anion gap. Thus, a normal renal response would be a negative urinary anion gap, generally in the range of 30 to

50 mEq/L. In such an instance, the acidosis is probably caused by gastrointestinal losses rather than by a renal lesion. The causes of acidosis characterized by a wide anion gap are listed in Table 28-10. In severe renal failure, inorganic compounds such as phosphates and sulfates are the major contributors to the increased anion gap. Organic compounds also accumulate in patients with severe renal failure. Ketoacidosis results from accelerated lipolysis and ketogenesis caused by relative or absolute insulin deficiency. Alcoholic ketoacidosis and starvation ketoacidosis result from the suppression of endogenous insulin secretion caused by inadequate carbohydrate ingestion. In addition, in alcoholic ketoacidosis, insulin resistance contributes to ketone formation. The syndrome of lactic acidosis results from impaired cellular respiration. Lactate is produced from the reduction of pyruvate in muscle, red blood cells, and other tissues as a consequence of anaerobic glycolysis. In situations of diminished oxidative metabolism, excess lactic acid is produced. This anaerobic state also favors a shift of keto acids to the reduced form, β-hydroxybutyrate. The nitroprusside reaction, which is catalyzed by the keto acids acetoacetate and acetone, is thus nonreactive in the setting of lactic acidosis. Lactic acidosis occurs most commonly in disorders characterized by inadequate oxygen delivery to tissues, such as shock, septicemia, and profound hypoxemia. Certain toxins may also sufficiently alter mitochondrial function and establish an effective anaerobic state. Some of these toxins may undergo metabolism into organic acids that can contribute to the generation of acidosis characterized by a large anion gap. Methanol is metabolized by alcohol dehydrogenase to formic acid. Ethylene glycol is metabolized to glycolic and oxalic acids. Salicylates are themselves acidic compounds and can cause acidosis characterized by a wide anion gap. The treatment of metabolic acidosis depends on the underlying cause and the severity of the manifestations. The rapid administration of parenteral sodium bicarbonate is generally indicated when the pH is less than 7.1 and hemodynamic instability is evident. Oral bicarbonate supplementation may be sufficient if the acidosis is caused by gastrointestinal bicarbonate loss or renal tubular acidosis (RTA). Treatment of organic acidosis should be directed at the underlying disorder. If the generation of the organic acid can be interrupted, the organic base pair may be metabolized, effectively regenerating bicarbonate. The acidemia of diabetic ketoacidosis, for example, can be effectively treated by administration of insulin, thereby inhibiting further ketogenesis. In lactic acidosis, therapy should be directed

Chapter 28—Fluid and Electrolyte Disorders toward improving tissue perfusion. In alcoholic and starvation ketoacidosis, administration of dextrose-containing intravenous fluids corrects the acidosis.

RENAL TUBULAR ACIDOSIS SYNDROMES Currently, three major RTA syndromes have been identified. These syndromes are discussed later, and their principal characteristics are described in Table 28-11.

Proximal Renal Tubular Acidosis Syndromes Proximal RTA occurs either alone or as the full Fanconi syndrome, with glycosuria, aminoaciduria, and phosphaturia. In proximal RTA, the threshold is reduced from 25 mmol/L to about 18 to 20 mmol/L (Fig. 28-9). Thus, a single-pulse loss of bicarbonate of about 850 to 900 mEq takes place.

Table 28-11 Renal Tubular Acidosis Syndromes Type

Locus

Defect

Proximal Hyperkalemic

S1-S3 CCD principal cell

Gradient limited

OMCD intercalated cells

↓ HCO3− threshold ↓ VM (−) leading to ↓ H+ secretion Three specific defects in H+ secretion

CCD, cortical collecting duct; OMCD, outer medullary collecting duct; S, segment; VM (−), negative transepithelial voltage in the OMCD.

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Proximal RTA occurs in a significant number of systemic diseases, most notably Wilson disease, cystinosis, and the gammopathies, especially light-chain disease; it is also seen in renal transplantation. Several molecular defects have been identified that also cause proximal RTA: • Mutations in the carbonic anhydrase II gene, which reduce its expression. It is transmitted as an autosomal-recessive syndrome characterized by osteopetrosis, cerebral calcification, and mental retardation. • Mutations in the SCLC4A4b gene that codes for the basolateral membrane sodium-bicarbonate transporter. This lesion is also an autosomal-recessive disease characterized by glaucoma, cataracts, band keratopathy, and psychomotor retardation. • Mutations in the SLC9A3 gene, which encodes the luminal NHE3 transport protein. Generalized Fanconi syndrome, which appears to be the consequence of a deficit in adenosine triphosphate (ATP) production in the proximal tubule, which reduces the activity of the basolateral sodium-potassium adenosine triphosphatase (Na+,K+-ATPase). This reduction is seen in severe phosphate depletion as well as in hereditary fructose intolerance. The focus of treatment is to enhance proximal bicarbonate reabsorption by reducing ECF volume. This reduction is achieved most commonly by salt restriction. An attempt to raise serum bicarbonate by oral bicarbonate therapy is counterproductive because it raises extracellular volume, enhances bicarbonaturia, provokes kaliuresis and phosphaturia, and produces hypokalemia and hypophosphatemia. Supplemental potassium to correct the hypokalemia is often necessary.

8.5 8.0

Urine pH

7.5 7.0 6.5 6.0 5.5 5.0 4.5

11 12 13 15 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Serum bicarbonate mmol/L

Figure 28-9 Bicarbonate titration curve in proximal renal tubular acidosis (RTA). Normal bicarbonate titration is shown by the solid line. Note that in patients with proximal RTA, bicarbonate excretion begins to appear in the urine when serum bicarbonate concentration exceeds 16 to 18 mmol/L, whereas in normal individuals, bicarbonate does not appear until serum bicarbonate is above 22 to 24 mmol/L. Below the threshold, patients with proximal RTA can reabsorb filtered bicarbonate nearly completely.

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Section VI—Renal Disease 8.5 8.0

Urine pH

7.5 7.0 6.5 6.0 5.5 5.0 4.5

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Serum bicarbonate mmol/L

Figure 28-10 Bicarbonate titration curve in gradient-limit renal tubular acidosis. Note the fixed bicarbonate excretion at any level serum bicarbonate (compare with Fig. 28-9).

Hyperkalemic Renal Tubular Acidosis Syndromes This second major group of RTA is theoretically caused by defects in principal cell function and takes three clinical forms. Pseudohypoaldosteronism I is inherited as an autosomal-recessive disease characterized by hyperkalemia, sodium wasting, and failure to thrive. Serum aldosterone is elevated, and the defect is unresponsive to administration of mineralocorticoids. A truncated form of epithelial sodium channel (ENaC) is found with low activity and massive sodium loss and is treated by large amounts of oral sodium. A second form, termed familial hyperkalemic hypertension, or Gordon syndrome, is characterized by hyperkalemia and sodium avidity, often accompanied by low renin and mild hypertension. The defect is responsive to loop diuretics and sodium restriction. Gordon syndrome is also responsive to thiazide diuretics, which inhibit the sodium-chloride co-transporter (NCC) in the distal tubule. This form of hyperkalemic RTA is caused by a loss of function mutation in WNK-4 (with no lysine), which inhibits NCC function (discussed in Chapter 26). Thus, the activity of the NCC is increased, reducing delivery to the collecting duct and consequent reduction in flow and voltage mediated potassium excretion. Because sodium reabsorption is increased in the distal tubule, hypercalciuria is prominent, and nephrocalcinosis occurs. The third form of hyperkalemic RTA is an acquired disease usually associated with interstitial fibrosis. In this form, serum aldosterone and renin are reduced even in the presence of hyperkalemia. The reason for this defect in aldosterone secretion and responsiveness to administered mineralocorticoids is unknown but suggests defects in principal cell function. The disease responds partially to furo-

semide and cautious liberalization of salt intake without provoking hypertension. The third major category of RTA is the so-called gradientlimited form and appears to be caused by a defect in outer medullary collecting duct function. Both principal and intercalated cell transports are defective. This disease is characterized by a fixed defect in bicarbonate excretion without apparent threshold (Fig. 28-10) and a fixed excretion of alkaline urine. Most commonly, the disease is the consequence of an inherited defect in the activity of the hydrogenATPase or potassium-hydrogen-ATPase. Acquired damage to the latter can also occur in autoimmune diseases, most notably Sjögren syndrome. This damage also occurs in sickle cell disease and primary hyperparathyroidism when these are associated with interstitial kidney damage. Drugs such as amphotericin and lithium may also cause damage. Impaired function of the basolateral band III chloride-bicarbonate exchanger is also thought to explain isolated cases because mutations have been found in the AEI gene that codes for it. Multiple mutations in the AEI gene may also occur, and in such cases, RTA is associated with ovalocytosis. In all cases of distal, gradient-limited RTA, hyperchlor emic acidosis occurs and is accompanied, because of sodium loss, by secondary hyperaldosteronism, leading to potassium depletion. In children, the syndrome impairs growth, and it may be associated with hypokalemic muscle paralysis, hypercalciuria, and nephrocalcinosis. Therapy consists of bicar bonate replacement as well as potassium replacement. Particularly in children, large amounts of bicarbonate may be required to ensure normal growth. Distal RTA is also complicated by a low urinary excretion of citrate, which leads to severe nephrocalcinosis.

METABOLIC ALKALOSIS A gain in base or loss of acid increases the bicarbonate concentration of the ECF. Normally, an elevation of the serum

Chapter 28—Fluid and Electrolyte Disorders bicarbonate concentration is corrected by excretion of the excess bicarbonate. The maintenance of metabolic alkalosis, therefore, implies a defect in the renal mechanism regulating bicarbonate excretion. This failure to excrete excess bicarbonate occurs by both physiologic responses to volume depletion, especially if hypercapnia and hypokalemia accompany the alkalosis, or by pathophysiologic responses, as occur in autonomous mineralocorticoid excess. The most common cause of metabolic alkalosis is gastric loss of hydrochloric acid by vomiting or mechanical drainage. Diuretic (thiazide and loop) use is commonly associated with metabolic alkalosis. Volume depletion associated with vomiting and diuretic use enhances proximal bicarbonate reabsorption. Enhanced activity of sodiumhydrogen exchange at this site, and consequent enhanced volume reabsorption, results in enhanced bicarbonate reabsorption (see Chapter 26). Volume depletion also leads to aldosterone secretion, which stimulates distal nephron hydrogen secretion and augments potassium secretion. Repair of the alkalosis under these circumstances requires administration of sodium chloride and potassium. Endogenous or exogenous mineralocorticoid excess (see Fig. 28-7) is unresponsive to volume administration as extracellular volume is expanded. The stimulation of distal hydrogen secretion by aldosterone is sufficient to limit bicarbonate excretion and stimulate potassium secretion. Repair of this disorder requires removal of the excess mineralocorticoid. In all these disorders, concomitant hypokalemia promotes the maintenance of metabolic alkalosis. Excessive alkali ingestion (e.g., milk-alkali syndrome) is an uncommon cause of metabolic alkalosis and results from impaired renal bicarbonate excretion caused by renal failure in the setting of excess alkali intake. In this instance, both hypercalcemia and vitamin D excess are thought to play roles in damaging the kidney. Removal of alkali often corrects the alkalosis, but renal function remains reduced if nephrocalcinosis is prominent. The determination of urinary chloride concentrations is helpful in formulating a rational approach to the diagnosis and treatment of metabolic alkalosis. In patients with hypertension since childhood, alkalosis, hypokalemia, and low urinary chloride, consideration should be given to Liddle syndrome. These features resemble mineralocorticoid excess, but renin and aldosterone levels are suppressed (pseudohypoaldosteronism). The disorder is inherited as an autosomal recessive disorder with mutations in the ENaC gene that result in deletion of the C-terminal region of the protein. This condition results in reduced degradation and increased density of sodium channels in the luminal membrane of the principal cells of the collecting duct (see Chapter 26). The clinical features are a consequence of the enhanced salt reab sorption, resultant volume expansion, and increased distal nephron potassium and proton secretion. Patients with high urinary chloride and alkalosis and who are hypertensive require work-up for hypercorticism, which may be autonomous, as in primary aldosteronism and Cushing disease or secondary to renal artery stenosis. Rarer still are the 11-β-hydroxylase deficiencies, or apparent mineralocorticoid excess (AME), in which reduced conversion of glucocorticoids reaching the collecting duct leads to overstimulation of ENaC. Another such syndrome of congenital hypertension and alkalosis is glucocorticoid-remediable

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aldosteronism (GRA), which is caused by a gene duplication in which the promoter for the 11-β-hydroxylase gene drives the aldosterone synthase gene and leads to adrenocorticotropic hormone–responsive aldosterone synthesis. In each of these instances, hyperactivity of ENaC leads to all clinical features of the syndrome. Normotensive or hypotensive conditions with alkalosis, hypokalemia, and high urinary chloride consist of two distinct forms: Bartter syndrome and Gitelman syndrome. Each syndrome involves distinct abnormalities in segmentspecific sodium chloride reabsorption, as well as differences in calcium and magnesium excretion. In Bartter syndrome (see Table 28-6), several disabling mutations in genes affecting the reabsorption of sodium chloride across the TAL have been characterized, including loss-of-function mutations in the NKCC2 co-transporter, the ROMK channel protein, and the basolateral chloride channel, and a gain in function mutation of the calcium-sensing receptor. Each of these mutations causes salt wasting, including enhanced calcium excretion, volume depletion, and, in many instances, reduced blood pressure. The reduction in ECF volume causes a secondary hyperaldosteronism, which, when coupled with enhanced sodium delivery to the collecting duct, causes potassium wasting and enhanced proton excretion. In Gitelman syndrome, disabling mutations in the DCT thiazide-sensitive sodium-chloride co-transporter have been described. The phenotypic characteristics of Gitelman syndrome in contradistinction to Bartter syndrome are the reduced calcium excretion and hypercalcemia observed, as might be expected from inhibition of the sodium-chloride co-transporter (see Chapter 26). The cause of hypermagnesuria in Gitelman syndrome is reduced expression of TRPM6 channel in the DCT.

RESPIRATORY ACIDOSIS Respiratory acidosis occurs with any impairment in the rate of alveolar ventilation. Acute respiratory acidosis occurs with a sudden depression of the medullary respiratory center (narcotic overdose), with paralysis of the respiratory muscles, and with airway obstruction. Chronic respiratory acidosis generally occurs in patients with chronic airway disease (emphysema), with extreme kyphoscoliosis, and with extreme obesity (pickwickian syndrome). The serum bicarbonate concentration is increased, the magnitude of which depends on the acuity and the severity of the respiratory disorder. The compensatory increase in serum bicarbonate in prolonged hypercapnia (>1 week) is primarily a function of bone buffering as the kidney plays a relatively minor role in the increase. Acute increases in the Pco2 result in somnolence, confusion, and, ultimately, carbon dioxide narcosis. Asterixis may be present. Because carbon dioxide is a cerebral vasodilator, the blood vessels in the optic fundi are often dilated, engorged, and tortuous. Frank papilledema may be present in patients with severe hypercapnic states. The only practical therapy of acute respiratory acidosis involves treatment of the underlying disorder and ventilatory support. In patients with chronic hypercapnia who develop an acute increase in the Pco2, attention should be directed toward identifying the factors that may have aggravated the chronic disorder. Diuretics often exacerbate the

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increase in serum bicarbonate and result in a mixed disorder of metabolic alkalosis and respiratory acidosis. Under these circumstances, acidification of the serum may be necessary to improve ventilation.

RESPIRATORY ALKALOSIS Respiratory alkalosis occurs when hyperventilation reduces the arterial Pco2 and consequently increases the arterial pH. Acute respiratory alkalosis is most commonly a result of pregnancy; it may also occur in damage to the respiratory centers, in acute salicylism, in fever and septic states,

in advanced liver disease, and when respiratory rate is increased in pneumonia, pulmonary embolism, and congestive heart failure. The disorder may be produced iatrogenically by injudicious mechanical ventilatory support. Chronic hyperventilation occurs in the acclimatization response to high altitudes cause by reduced ambient partial pressure of oxygen. Acute hyperventilation is characterized by lightheadedness, paresthesias, circumoral numbness, and tingling of the extremities. Tetany occurs in severe cases. When anxiety provokes hyperventilation, air rebreathing with a paper bag generally terminates the acute attack.

Prospectus for the Future • Identification of additional gene mutations informative about the renal regulation of water and solute transport

References Andreoli TE: Water: Normal balance, hyponatremia and hypernatremia. Ren Fail 22:711-735, 2000. Cao G, Hoenderop JGJ, Bibdels RJM: Insight into the molecular regulation of the epithelial magnesium channel TRPM6. Curr Opin Nephrol Hypertens 17:373-378, 2008. Gamba G: Role of WNK kinases in regulating tubular salt and potassium transport and in the development of hypertension. Am J Physiol Renal Physiol 288:F245F252, 2005.

• Design of small molecules to inhibit salt and water transport in specific nephron segments for the treatment of hypertension and edema

Ellison DH, Berl T: Clinical practice: The syndrome of inappropriate antidiuresis. N Engl J Med 356:2064-2072, 2007. Kokko JP: Fluid and electrolytes. In Goldman L, Bennett JC (eds): Cecil Textbook of Medicine, 21st ed. Philadelphia, WB Saunders, 2000, pp 540-567. Tannen RL: Dyskalemias. In Massry SG, Glasscock FJ (eds): Textbook of Nephrology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 295-307.

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29

VI

Glomerular Diseases Jamie P. Dwyer and Julia B. Lewis

E

ach human kidney contains nearly 1 million glomerular capillary tufts, which derive from an afferent arteriole and are held together by the mesangial matrix. The glomerular capillary tufts drain into an efferent arteriole forming an arteriolar portal system. Fenestrated endothelial cells, the glomerular basement membrane (GBM), and delicate foot processes extending from epithelial podocytes, which are interconnected to each other by slit diaphragms (Web Fig 29-1), form a selective filtration barrier between the capillary blood and urinary space (Web Fig 29-2A). Each glomerular tuft has an associated renal tubule that drains into the urologic system. Nearly one fourth of the blood of each heartbeat is filtered by the kidney (about 120 to 180 L per 24 hours). Remarkably, despite the 12,000 to 18,000 g of protein filtered by the capillaries each day, less than 150 mg appears in urine. This is accomplished in part by the negatively charged GBM and the 4-nm slit-pore membranes restricting the movement of large or negatively charged proteins. Therefore, the glomerulus serves as a size- and chargeselective barrier to the movement of proteins and cells from the capillary blood into the urinary space. The glomerulus can be injured by a variety of means, including genetic mutations producing familial diseases, immune-mediated inflammation, vascular injury, deposition of abnormal proteins, and infection. These injuries result in diverse glomerular diseases manifesting clinically as proteinuria, hematuria, pyuria, and vascular changes.

GFR. If the loss of GFR (seen as a rise in serum creatinine) occurs over days, acute nephritis is called rapidly progressive glomerulonephritis (RPGN) and is associated with crescentic glomerulonephritis on renal biopsy. Patients with the clinical syndrome of RPGN in whom the disease extends to the lungs are classified as having a pulmonary-renal syndrome (Table 29-2). In nephrotic syndrome, the patient excretes more than 3.5 g of protein in a 24-hour urine collection and has edema, hypoalbuminemia, and hypercholesterolemia. In long-standing nephrotic syndrome, decreased GFR and hypertension often develop (e.g., in diabetic nephropathy). Many glomerular diseases present with microscopic or gross hematuria and either no or mild proteinuria. Hematuria may be the only manifestation of some glomerular diseases throughout their course, as in thin basement membrane disease, or may be an early manifestation that progresses over time to involve other clinical signs such as decreased GFR, as in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. When abnormal proteins, such as paraproteins, are deposited in or accumulate in the glomerulus in glomerular deposition diseases, the clinical manifestations can range from asymptomatic mild proteinuria to severe nephrotic syndrome. Glomerular vascular syndromes occur in patients in whom the injury is primarily

Clinical Syndromes Glomerular diseases can have diverse clinical manifestations, including hematuria (Web Fig. 29-3), proteinuria, pyuria (Web Fig. 29-4), hypertension, fluid retention, edema, and a reduction in glomerular filtration rate (GFR). Glomerular diseases can be acute, developing over days; subacute, developing over weeks; or chronic, developing over months or years. Distinct clinical syndromes have been described; however, these syndromes are not always mutually exclusive (Table 29-1) The acute nephritic syndrome is characterized by hypertension, hematuria, edema, red blood cell (RBC) casts (Fig. 29-1) or dysmorphic RBCs (Web Fig. 29-5), modest proteinuria (1 to 2 g per 24 hours), and decreased

Figure 29-1 Immunofluorescence demonstrating a linear pattern of immunoglobulin G.

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Table 29-1 Clinical Syndromes Acute Nephritic Syndromes Poststreptococcal glomerulonephritis Subacute bacterial endocarditis Lupus nephritis* (WHO class III or IV) Anti-GBM disease, Goodpasture syndrome ANCA-associated vasculitis (Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome)* Cryoglobulinemia* IgA nephropathy Henoch-Schönlein purpura Membranoproliferative glomerulonephritis Nephrotic Syndromes Minimal change disease FSGS MGN Diabetic nephropathy Lupus nephritis (WHO class V) ANCA-associated vasculitis Deposition diseases Nail-patella syndrome Fabry disease Syphilis (MGN) Schistosomiasis (MPGN, FSGS, amyloid) Primarily Hematuria Manifested Glomerular Diseases IgA nephropathy Thin basement membrane disease Alport syndrome MGPN Lupus nephritis (WHO class II or III) ANCA-associated vasculitis (early)* Sickle cell disease Glomerular Deposition Diseases Light-chain deposition disease Amyloidosis Fibrillary glomerulonephritis, immunotactoid glomerulonephritis Fabry disease Glomerular Vascular Syndromes Hypertensive nephrosclerosis Cholesterol emboli Sickle cell disease Thrombotic thrombocytopenia purpura, hemolytic uremic syndrome Antiphospholipid antibody syndrome ANCA-associated vasculitis Henoch-Schönlein purpura Cryoglobulinemia* Amyloidosis Ischemic nephropathy Infection-Associated Syndromes Poststreptococcal glomerulonephritis Subacute bacterial endocarditis HIV (FSGS) Hepatitis B and C (MGN and MPGN, respectively) Syphilis Leprosy Malaria Schistosomiasis *May present as a pulmonary-renal syndrome. ANCA, antineutrophil cytoplasmic antibody; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; IgA, immunoglobulin A; MGN, membranous glomerulonephritis; MPGN, membranoproliferative glomerulonephritis; WHO, World Health Organization.

Table 29-2 Differential Diagnosis of Rapidly Progressive Glomerulonephritis Linear Immune Staining Anti-GBM disease Goodpasture syndrome Rarely membranous glomerulonephritis Granular Immune Staining Subacute bacterial endocarditis (past infectious) Lupus nephritis Cryoglobulinemia Membranoproliferative glomerulonephritis (type II more than type I) Immunoglobulin A nephropathy, Henoch-Schönlein purpura Idiopathic No Immune Staining (Pauci-immune) Antineutrophil cytoplasmic antibody–associated vasculitis (Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome) Idiopathic

localized to the renal vasculature and is usually associated with hematuria and mild proteinuria. Lastly, a wide variety of infections can produce inflammatory reactions in the glomerulus, ranging from nephritic syndrome with RPGN to mild proteinuria or nephrotic syndrome. The classification of glomerular diseases is hampered by the fact that an individual glomerular disease can present with more than one constellation of clinical signs or symptoms. For example, lupus nephritis can present as nephrotic syndrome, rapidly progressive glomerulonephritis, or asymptomatic hematuria. Hence, all classifications of glomerular diseases are complex and somewhat arbitrary. Each of the major glomerular diseases is discussed next, and potential alternate manifestations are noted (see Table 29-1).

Evaluation of Glomerular Diseases A detailed history and physical examination can help clarify the differential diagnosis of glomerular lesions. Onset and timing may be important (e.g., nephrotic syndrome in a child suggests minimal change nephropathy). Associated physical examination findings may add to the diagnosis (e.g., Raynaud phenomenon in lupus nephritis, livedo reticularis in cholesterol emboli). Assessment for anemia, thrombocytopenia, eosinophilia, microangiopathic hemolysis, serologies for antinuclear antibody (ANA), ANCAs, anti-GBM antibody, antibodies to hepatitis B and C, HIV, rheumatoid factor, anti-DNAse B, antistreptolysin O (ASO) titer, cryo globulin, and monoclonal proteins may help in narrowing the diagnostic possibilities. Urine microscopy is a critical element in the evaluation of a patient with glomerular diseases and may reveal hematuria, RBC casts, oval fat bodies or fatty casts (Web Fig. 29-6), or proteinuria. Measurement of 24-hour creatinine clearance and proteinuria helps distinguish the presence or absence of nephrotic syndrome and assesses GFR. Ultimately, a specific diagnosis may rely on a renal biopsy. Indications for renal biopsy vary from patient to patient and between countries. Renal biopsy allows one

Chapter 29—Glomerular Diseases

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Table 29-3 Glomerular Diseases Associated with Hypocomplementemia Poststreptococcal glomerulonephritis Lupus nephritis (acute) Cholesterol emboli Membranoproliferative glomerulonephritis, hepatitis C Subacute bacterial endocarditis Cryoglobulinemia Shunt nephritis

Acute Nephritic Syndromes Figure 29-2 Glomerulus demonstrating crescent formation.

to make a diagnosis and can be determined by light microscopy if the disease is focal (involving 50% of glomeruli), segmental (involving a portion of a glomerulus) or global (involving the entire glomerulus). It can also demonstrate so-called crescent formation (Fig. 29-2), which is the pathologic hallmark of rapidly progressive glomerulonephritis. Immunofluorescence microscopy can identify types of immunoglobulin deposition and location (e.g., linear immunoglobulin G [IgG] staining in Goodpasture syndrome (Fig. 29-1). There may be minimal or no immune deposition (pauci-immune glomerulonephritis). Electron microscopy can show the location of electron-dense deposits (e.g., subepithelial deposits in poststreptococcal glomerulonephritis (Web Fig. 29-7) or subendothelial deposits in proliferative lupus nephritis (Web Fig. 29-8).

General Treatment Guidelines for Glomerular Disease Specific therapies for the different glomerular disease are noted next. In all forms of glomerular disease, treatment of hypertension, if present, is indicated with a target blood pressure of 130/80 mm Hg. For many glomerular diseases, including all those associated with proteinuria, treatment with drugs that inhibit the renin-angiotensin system is recommended. It has also been suggested that accelerating therapy to maximally reduce proteinuria should be a goal. Volume overload, manifested by edema, should be treated by reduction in salt and water intake and judicious use of diuretics. Hypercholesterolemia should be controlled with dietary modification and pharmacologic therapy. If a hypercoagulable state exists, anticoagulation may be necessary. Every effort should be made to avoid exposure to nephrotoxins because patients with glomerular disease may be at increased risk for acute kidney injury. Lastly, close monitoring of renal function by a specialist is indicated in most cases.

POSTSTREPTOCOCCAL GLOMERULONEPHRITIS Poststreptococcal glomerulonephritis (PSGN) can occur as a postinfectious complication of skin and throat infections with particular M types (nephritogenic strains) of streptococci. PSGN due to streptococcal pharyngitis occurs in fewer than 5% of people infected, typically 1 to 3 weeks after the pharyngitis. Streptococcal impetigo is a less common cause of PSGN than pharyngitis but leads to PSGN in as many as 50% of infected people 2 to 6 weeks after the impetigo. In undeveloped countries, PSGN can occur in a epidemic form, but in Western countries, it typically occurs sporadically in the summer and autumn. PSGN can occur in adults but usually occurs in children between the ages of 2 and 14 years. Patients present classically with acute nephritis, characterized by hematuria, pyuria, RBC casts, edema, hypertension, systemic symptoms of headache and malaise, flank pain due to renal capsular swelling, and oliguric renal failure. Because the hematuria occurs after the pharyngitis, it is called metapharyngitic or postpharyngitic hematuria. Five percent of children and 20% of adults have nephrotic range proteinuria. A subclinical disease has also been reported, characterized by asymptomatic microscopic hematuria. Early in the course, 90% of patients will have decreased levels of C3 and CH50 with normal levels of C4. Patients with PSGN must be distinguished from other glomerular diseases associated with hypocomplementemia (Table 29-3). Rheumatoid factor, cryoglobulins, and ANCA may all be positive. Increased titers of ASO antibodies (30%), anti-DNAase (70%) or antihyaluronidase antibodies (40%) can help confirm the diagnosis. Histologically, the kidney demonstrates a diffuse proliferative glomerulonephritis with hypercellularity of mesangial and endothelial cells (Web Figs. 29-9 and 29-10), glomerular infiltrates of polymorphonuclear leukocytes, and granular, “lumpy-bumpy” subendothelial and subepithelial deposits of IgG, IgM, and complement. Treatment is supportive and may require renal replacement therapy. Antibiotic therapy does not alter the course of PSGN. Immunosuppressive therapy is also ineffective. Complete recovery occurs in 90% to 95% of patients; in children, recovery is usually seen within 3 to 6 weeks of the onset of nephritis, whereas in adults, proteinuria and hematuria may continue for 1 to 2 years. End-stage renal disease (ESRD) is uncommon, occurring in 1% to 3% of adults and rarely in children.

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SUBACUTE BACTERIAL ENDOCARDITIS Endocarditis-associated glomerulonephritis is a complication of subacute bacterial endocarditis. Patients present with hematuria, pyuria, and mild proteinuria, or less commonly with RPGN. Laboratory examination reveals an elevated erythrocyte sedimentation rate, hypocomplementemia, a positive rheumatoid factor, cryoglobulinemia (type III), and anemia. Renal biopsy reveals a focal proliferative glomerulonephritis with abundant mesangial, subendothelial, and subepithelial deposits of IgG, IgM, and complement. Patients who present with RPGN have crescents on renal biopsy. Embolic infarcts or abscesses may also be present. Treatment is antibiotics for 4 to 6 weeks, and the prognosis is good. Glomerulonephritis can also occur in patients with infected ventriculoatrial and ventriculoperitoneal shunts (shunt nephritis); pulmonary, intra-abdominal, pelvic, or cutaneous infections; and infected vascular prostheses. Treatment is eradication of the infection.

LUPUS NEPHRITIS Sixty percent of adults and 80% of children with systemic lupus erythematosus (SLE) develop renal abnormalities. The clinical manifestations and treatment of lupus nephritis are closely linked to the renal pathology (Table 29-4). Clinical signs and laboratory data can include hematuria, proteinuria, RBC casts, hypertension, hypocomplementemia, and anti–double-stranded DNA (anti-dsDNA) antibodies. Renal biopsy is critical to distinguish the variants of lupus nephritis (Web Fig. 29-11), and patients with lupus often undergo multiple biopsies as their lupus-related renal lesions may vary over time. The World Health Organization (WHO) has outlined distinct patterns of lupus-related glomerular injury (see Table 29-4). WHO class I lesions have minimal clinical manifestations and either normal histology or minimal mesangial deposits. Prognosis is excellent, and no treatment is required. WHO class II nephritis demonstrates mesangial immune complex deposition with mesangial proliferation, but few clinical renal manifestations, normal renal function, and a good prognosis. Specific treatment is generally not necessary. WHO class III lesions demonstrate focal lesions

with proliferation and scarring (focal proliferative lupus nephritis), and patients with class III lesions have diverse clinical courses. Patients can present with hypertension, hematuria, proteinuria, nephrotic syndrome (25% to 33%), or elevated serum creatinine (25%). Some patients with only mild focal proliferation involving a small percentage of glomeruli respond to steroid therapy alone with an excellent prognosis. Others with more severe proliferation involving a greater percentage of glomeruli have a worse prognosis, and therapy with steroids and other immunosuppressive drugs (cyclophosphamide, mycophenolate) is required. WHO class IV nephritis demonstrates global, diffuse proliferative lesions involving most of the glomeruli (diffuse proliferative lupus nephritis). Clinically, patients present with the most severe manifestations, including RPGN, hematuria, RBC casts, hypertension, proteinuria (50% nephrotic range), and declining renal function. Without treatment, WHO class IV lesions have the worst prognosis, and therapy with steroids and immunosuppressive drugs is recommended. If remission is achieved (defined as a return to near-normal renal function and proteinuria 10 years) type 1 diabetes who have other complications, such as peripheral and autonomic neuro pathy, nephropathy, and retinopathy, GI complaints are also common within the first decade of diagnosis. Diabetic gastroparesis appears to occur as a result of permanent neuropathy of autonomic and enteric nerves, transitory variations in glycemic control, or a combination of both. Idiopathic gastroparesis is also common and comprises those instances with no clearly identifiable cause. Up to one third of these patients have virus-induced gastroparesis, with viral infiltration of the myenteric plexus in the stomach. Patients who have undergone gastric surgery, especially those having had preoperative gastric outlet obstruction as a complication of PUD, are also commonly affected by

Table 37-4 Causes of Delayed Gastric Emptying Mechanical Causes Peptic ulcer disease, scarred pylorus Malignancy: gastric cancer, gastric lymphoma, pancreatic cancer Gastric surgery: vagotomy, gastric resection, roux-en-Y anastomosis Crohn disease Endocrine and Metabolic Causes Diabetes mellitus Hypothyroidism Hypoadrenal states Electrolyte abnormalities Chronic renal failure Medications Anticholinergics Opiates Dopamine agonists Tricyclic antidepressants Abnormalities of Gastric Smooth Muscle Scleroderma Polymyositis, dermatomyositis Amyloidosis Pseudo-obstruction Myotonic dystrophy Neuropathy Scleroderma Amyloidosis Autonomic neuropathy Central Nervous System or Psychiatric Disorders Brainstem tumors Spinal cord injury Anorexia nervosa Stress Miscellaneous Idiopathic gastroparesis Gastroesophageal reflux disease Nonulcer (functional) dyspepsia Cancer cachexia or anorexia

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Section VII—Gastrointestinal Disease

gastroparesis. Finally, Parkinson disease, rheumatologic disorders, hypothyroidism or hyperthyroidism, chronic intestinal pseudo-obstruction, and a variety of paraneoplastic syndromes can also produce gastroparesis. The diagnostic evaluation of delayed gastric emptying should focus on excluding structural and metabolic abnormalities. Endoscopy is the preferred initial test to rule out mechanical gastric outlet obstruction, and a small bowel follow-through radiograph may be useful to exclude small bowel lesions. Serum electrolytes, blood cell counts, and thyroid studies should also be performed. When these studies are negative, radionuclide scintigraphy (gastricemptying scan) using a mixed solid-liquid meal can quantitate delayed gastric emptying. Assessment of solid emptying is more clinically relevant than liquid emptying. In especially difficult cases, GI manometry and electrogastrography may help in the diagnosis. Managing gastroparesis begins with identifying and treating potentially correctable causes. Medications that reduce gastric emptying, such as narcotics, anticholinergics, and tricyclic antidepressants, should be avoided. Because liquids empty easier than solids, and because liquid emptying is often preserved in patients with gastroparesis, simple dietary modifications may be helpful in treatment. The diet should be modified to include blenderized foods and liquid supplements. High-fat and fiber-rich foods should be avoided because they inhibit gastric emptying under normal conditions and are less likely to empty. Medical options are limited and involve the use of prokinetic drugs, which are agents that improve transit in the GI tract. Metoclopramide is a dopamine-2 receptor antagonist that also facilitates the release of acetylcholine from cholinergic nerve terminals in the gut, thereby accelerating gastric emptying. The efficacy of metoclopramide is inconsistent, and adverse effects and the development of tolerance complicate long-term therapy. Adverse effects occur in up to 20% of patients and include drowsiness, anxiety, fatigue, insomnia, restlessness, agitation, extrapyramidal effects, galactorrhea, and menstrual irregularities. The typical dosage is 10 mg, 20 to 30 minutes before meals and at bedtime, although doses as high as 80 mg or as low as 20 mg may be used daily. Doses should be reduced for patients with renal failure. Domperidone, another dopamine receptor antagonist with prokinetic properties, has similar efficacy to metoclopramide in the treatment of delayed gastric emptying but is currently not available in the United States. Cisapride, an agent that increases gastric motor activity by facilitating the release of acetylcholine at the myenteric plexus, is no longer routinely available in the United States and other countries because of serious adverse effects, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and prolongation of the QT interval, which have been reported when cisapride is administered with other drugs that inhibit cytochrome P-450. Erythromycin is a macrolide antibiotic that stimulates smooth muscle motilin receptors located at all levels of the GI tract. The prokinetic effects of erythromycin are related to its ability to mimic the effect of the GI peptide motilin to stimulate smooth muscle contraction, which accounts for the acceleration of solid and liquid gastric emptying. Erythromycin may dramatically improve gastric emptying in patients with severe diabetic gastroparesis when given acutely

at an intravenous dose of 1 to 3 mg/kg every 8 hours. Longterm use of the drug at a dose of 250 to 500 mg orally every 8 hours in patients with gastric stasis is of limited efficacy because of tachyphylaxis and side effects. Endoscopic botulinum toxin A injection into the pyloric sphincter has also been reported in the treatment of delayed gastric emptying in small studies, but long-term benefit has not been proved. In patients who are refractory to these measures, surgical placement of a jejunal tube, with or without a venting gastrostomy, may be necessary. Total parenteral nutrition is rarely indicated. Surgical gastrectomy should only be considered in patients with refractory postsurgical gastric stasis. Gastric pacemakers and other prokinetics, specifically new serotonin-receptor agonists, are under investigation and may be options in the future.

Rapid Gastric Emptying Rapid gastric emptying is a far less common clinical problem than delayed gastric emptying. Dumping syndrome describes the alimentary and systemic manifestations of early delivery of large amounts of osmotically active food to the small intestine. Dumping syndrome is usually seen when the normal reservoir, grinding, and sieving properties of the stomach are disrupted, most commonly following surgery for obesity (Roux-en-Y gastric bypass) or PUD. The accelerated emptying of hypertonic boluses of nutrient material into the small intestine results in splanchnic vasodilation and release of vasoactive peptides. Early dumping symptoms, occurring about 30 minutes after a meal, include epigastric fullness and pain, nausea, vomiting, early satiety, and vasomotor features such as flushing, palpitations, and diaphoresis. Later symptoms, such as diaphoresis, tremulousness, and weakness, occur about 2 hours after a meal and may be caused by hypoglycemia from rebound hyperinsulinemia. Treatment of dumping syndrome involves dietary manipulation to decrease the volume and osmotic load emptied into the intestine. Frequent small feedings of meals low in carbohydrates, separation of liquid and solid intake, and avoidance of hypertonic fluids and lactose are usually helpful. When these measures fail, administration of octreotide at a dose of 25 to 50 mcg subcutaneously 30 minutes before meals may be helpful. Octreotide acts by slowing gastric emptying and intestinal transit as well as by inhibiting the release of insulin. Surgical procedures to slow gastric emptying have limited success.

Gastric Volvulus Gastric volvulus occurs when the stomach twists on itself. This event may be transient, producing few if any symptoms, or may lead to obstruction or even ischemia and necrosis. Primary gastric volvulus, seen in one third of the patients, occurs below the diaphragm when the stabilizing ligaments are too lax as a result of congenital or acquired causes. Secondary gastric volvulus occurs above the diaphragm in association with paraesophageal hernias or other diaphragmatic defects. Acute gastric volvulus produces sudden, severe pain of the upper abdomen or chest, persistent retching

Chapter 37—Diseases of the Stomach and Duodenum producing scant vomitus, and the inability to pass a nasogastric tube. This combination of symptoms, also known as Borchardt triad, should lead to a strong clinical suggestion of acute gastric volvulus. Chronic gastric volvulus may be associated with mild and nonspecific symptoms, such as epigastric discomfort, heartburn, abdominal fullness or bloating, and borborygmi, especially after meals. The diag-

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nosis of gastric volvulus is made by upper GI series demonstrating an abrupt obstruction at the site of the volvulus. Acute gastric volvulus requires emergency surgical evaluation because of the substantial risk for mortality related to gastric ischemia or perforation. Treatment consists of surgical gastropexy and repair of any associated paraesophageal hernia.

Prospectus for the Future Our understanding of a significant number of issues involving gastroduodenal pathologic mechanisms and therapeutics will continue to evolve in the next few years. Select goals include the following: • Development of variations in the structure and delivery of antisecretory therapy, leading to formulations designed to provide increased rapid onset of action and to improve effectiveness in individuals who are unable to take medications by mouth or those with dysmotility or malabsorption • Further clarification of the optimal H. pylori treatment regimen given increased antibiotic resistance profiles

References Chan FK, Graham DY: NSAIDs, risks, and gastroprotective strategies: Current status and future. Gastroenterology 134:1240-1257, 2008. Fuccio L, Minardi ME, Rocco MZ, et al: Meta-analysis: Duration of first-line proton-pump inhibitor-based triple therapy for Helicobacter pylori eradication. Ann Intern Med 147:553-562, 2007. Olsen KM, Devlin JW: Comparison of the enteral and intravenous lansoprazole pharmacodynamic responses in critically ill patients. Aliment Pharmacol Ther 28:326-333, 2008.

and the goal of improving patient compliance to treatment • Procurement of evidence-based data to aid in managing stress-related mucosal ulcerations in critically ill patients • Elucidation of the exact nature and strength of the association between COX-2–selective inhibitors and cardiovascular disease and future development of safer NSAIDs • Further insight into the mechanism governing GI motility and the development of new agents for the treatment of motility disorders

Papatherodoridis GV, Sougioultzia S, Archimandritis AJ: Effects of Helicobacter pylori and nonsteroidal anti-inflammatory drugs on peptic ulcer disease: A systematic review. Clin Gastroenterol Hepatol 4:130-142, 2006. Park MI, Camilleri M: Gastroparesis: clinical update. Am J Gastroeterol 101:11291139, 2006. Vergara M, Catalan M, Gisbert JP, et al: Meta-analysis: Role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users. Aliment Pharmacol Ther 21:1411-1418, 2005.

VII

Chapter

38

Inflammatory Bowel Disease Christopher S. Huang and Francis A. Farraye

A

lthough a significant number of infectious organisms and noninfectious processes (e.g., medications, radiation, ischemia) can result in intestinal inflammation, the term inflammatory bowel disease (IBD) generally refers primarily to two idiopathic diseases: ulcerative colitis and Crohn disease. The diagnosis of IBD is made by incorporating clinical, endoscopic, radiologic, and histologic information. Ulcerative colitis is characterized by inflammatory changes that involve the colonic mucosa in a continuous superficial fashion, generally starting in the rectum and extending proximally. Depending on the extent of the disease, ulcerative colitis can be divided into proctitis (rectum only), proctosigmoiditis, left-sided colitis (extending to the splenic flexure), or pancolitis. This classification is important for both prognostic and therapeutic reasons. Unlike ulcerative colitis, Crohn disease can involve any segment of the gastrointestinal system, often in a discontinuous fashion. It is characterized by transmural inflammation, which results in significant complications such as abscesses, fistulas, and strictures. Despite the chronic nature of these two diseases, new and emerging targeted anti-inflammatory treatments hold great promise in helping to reduce morbidity and improve the quality of life of individuals with IBD.

Epidemiology In the United States, about 1.4 million individuals have IBD, and the overall incidence of new cases of IBD is about 3 to 10 new cases per 100,000 people. During the past several decades, the incidence of ulcerative colitis has remained stable, whereas the incidence of Crohn disease has gradually increased. The prevalence of IBD is essentially 10-fold higher, between 30 and 100 per 100,000 people. A bimodal age of presentation exists, with an initial peak between the second and fourth decades of life followed by another peak at about the sixth decade of life. Both sexes are equally affected. The incidence and prevalence of IBD reflect the genetic and environmental factors that contribute to these disorders. 430

For example, both diseases are common in northern climates, among whites, particularly in populations with Northern European ancestry, including North Americans, South Africans, and Australians. Individuals of Ashkenazi Jewish descent have also been found to have a twofold to eightfold increased risk for these disorders compared with non-Jews. Although the prevalence and incidence rates of IBD are lowest in Hispanics and Asians, IBD can occur in any ethnic or racial group from anywhere in the world.

Causes Although the causes of IBD remain unknown, recent advances in the understanding of the genetic, immunologic, and environmental factors are beginning to decipher the etiologic factors of these complex disorders. Currently, it is believed that IBD results from an inappropriate, overactive mucosal immune response to commensal intestinal bacteria in genetically susceptible individuals.

GENETIC FACTORS About 5% to 20% of patients with IBD have a first-degree relative with the disease, and first-degree relatives of IBD patients have about a 10- to 15-fold increased risk for developing IBD, predominantly with the same disease as the proband. A positive family history is generally more frequently observed in patients with Crohn disease than in patients with ulcerative colitis, suggesting that genetic factors contribute more significantly in the etiology of Crohn disease. Through advances in genome-wide association studies, several susceptibility loci on multiple chromosomes have been linked to IBD, supporting a polygenic cause to these disorders. Polymorphisms in the NOD-2 gene (also known as CARD-15, located on chromosome 16) were the first definitive genetic risk factors identified for Crohn disease. Homozygous mutations of the NOD-2 gene are associated with a greater than 20-fold increase in susceptibility for Crohn disease. Defects in the NOD-2 protein appear

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to result in abnormal intestinal immune responses to bacterial cell wall components. These gene mutations are estimated to account for about 15% to 25% of the cases of Crohn disease and are linked predominantly to fibrostenotic terminal ileal disease. Another gene of interest is the IL-23R gene on chromosome 1, which has also been shown to be strongly associated with IBD, particularly Crohn disease. Disease-associated IL-23R polymorphisms have also been reported in patients with ulcerative colitis, psoriasis, and ankylosing spondylitis. Many other genes have been uncovered by genome-wide association studies, such as OCTN, DLG-5, ICAM-1, and TLR-4, and are currently under investigation for their potential involvement in the pathogenesis of IBD.

ized. It has been postulated that poor sanitation, food contamination, and crowded living conditions are associated with helminthic infection, which leads to regulatory T-cell conditioning and stimulation of IL-10 and transforming growth factor-β production by mononuclear cells, thereby preventing intestinal inflammation. However, to date, the only environmental factor clearly associated with IBD is tobacco smoking. Smoking seems to be protective against ulcerative colitis, whereas smokers with Crohn disease have more aggressive disease than do nonsmokers. No dietary triggers have been found to cause IBD, but elemental diets and diversion of the fecal stream can reduce recurrence of inflammation in Crohn disease.

IMMUNOLOGIC FACTORS

Clinical Features of Ulcerative Colitis

Profound alterations in mucosal immunology have been demonstrated in patients with IBD. In the normal immunologic state of the intestine, recently activated lymphoid tissue is abundant within the mucosal compartment. This state has been described as controlled, or physiologic, inflammation, which has likely developed in response to constant encounters with antigenic substances (derived from host microbial flora, or dietary and environmental sources) that have crossed the epithelial barrier from the luminal environment. Indeed, one of the main functions of the intestinal immune system is to discriminate noxious or harmful substances and organisms from nonharmful ones. As a result, a large and well-maintained network of many different mucosal immune cells exists, including cells involved in reducing immune responses (regulatory cells) and those involved in activating immune responses. In IBD, this homeostatic balance, or immune tolerance, is dysregulated, resulting in overactivation of the immune system. Crohn disease, for example, reflects an excessive and persistent CD4 helper T-cell subtype 1 (TH1) immune response to components of commensal bacterial flora. The TH1 cytokine profile, including interferon-γ, interleukin-2 (IL-2), IL-12, and tumor necrosis factor-α (TNF-α), is elevated in patients with Crohn disease. The cytokine profile of ulcerative colitis is atypical, with greater expression of IL-5 and IL-13 present, cytokines characteristically associated with a TH2 response. More recently, non-TH1/ TH2 pathways have been identified as being potentially important in the pathogenesis of IBD. IL-23, for example, has been recognized as an inducer of a subset of proinflammatory T cells (TH17) that secrete high levels of IL-17 and play an important role in mediating inflammation in murine models of colitis. IL-17 expression has been shown to be upregulated in active IBD, both Crohn disease and ulcerative colitis.

ENVIRONMENTAL FACTORS Although believed to be important, the role of environmental factors in IBD pathogenesis remains poorly understood. Many infectious agents, including Mycobacteria paratuberculosis and measles virus, have been implicated in IBD, but none fulfills the criteria of true pathogens. Environmental factors are suspected because the disease is more common in industrialized countries, and the frequency has been increasing in countries that are becoming more industrial-

Ulcerative colitis is characterized by chronic inflammation of the mucosal surface that involves the rectum (proctitis) and extends proximally through the colon in a continuous manner. The extent and severity of the colonic inflammation determine prognosis and presentation (insidious versus acute onset). Most patients initially exhibit diarrhea, abdominal pain, urgency to defecate, rectal bleeding, and the passage of mucus per rectum. Patients occasionally have extraintestinal manifestations (see later discussion) before they develop intestinal symptoms. About 40% to 50% of patients have proctitis or proctosigmoiditis, 30% to 40% have left-sided colitis (disease extending to the splenic flexure), and the remaining 20% to 25% have pancolitis. Of the patients who initially show proctitis or proctosigmoiditis, about 15% develop more extensive disease over time. The typical clinical course is of chronic intermittent exacerbations, followed by periods of remission. Signs of a worsening clinical course include the development of abdominal pain, dehydration, fever, and tachycardia. Clinical features, including bowel frequency, fever, increased heart rate, and blood in stools, as well as the presence of anemia and an elevated erythrocyte sedimentation rate (ESR) or C-reactive protein, have been used to assess severity of ulcerative colitis.

MAJOR COMPLICATIONS Toxic Megacolon and Perforation Toxic megacolon is characterized by gross dilation of the large bowel associated with fever, abdominal pain, dehydration, tachycardia, and bloody diarrhea, which may require urgent surgical intervention. Perforation can occur in the setting of toxic megacolon or in patients with active colitis, especially those taking corticosteroids.

Gastrointestinal Hemorrhage and Anemia Although massive hemorrhage is uncommon, this complication is an indication for surgical intervention. Anemia commonly occurs and is caused by chronic blood loss from the involved colonic mucosa as well as bone marrow suppression from the inflammatory condition.

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Colonic Adenocarcinoma The risk for colon cancer is increased in patients with ulcerative colitis, the magnitude of which is related to the extent and duration of disease. Colon cancer risk is increased 10- to 20-fold (if disease extends proximal to the sigmoid colon) after 8 years of disease compared with that in unaffected individuals. Colonoscopy with surveillance biopsies are recommended every 2 years after 8 to 10 years of disease in patients with pancolitis and after 12 to 15 years in patients with left-sided colitis, followed by yearly examinations after 20 years of disease. Proctitis is not associated with an increased cancer risk. Patients with IBD and primary sclerosing cholangitis (PSC) appear to be at particularly increased risk, and yearly surveillance is recommended after the initial diagnosis of PSC. A minimum of 33 “random” mucosal biopsy samples are recommended during the colonoscopic examination, in addition to targeted samples of circumscript lesions. The use of chromoendoscopy and other enhanced imaging techniques increases the detection of dysplastic lesions in patients with ulcerative colitis. Colectomy is indicated in patients with flat high-grade dysplasia, multifocal flat low-grade dysplasia, possibly unifocal flat low-grade dysplasia, or evidence of colorectal cancer. Polypoid dysplasia entirely removed by polypectomy without flat dysplasia elsewhere in the colon can be managed with continued surveillance colonoscopy.

Clinical Features of Crohn Disease Crohn disease may involve any portion of the gastrointestinal tract, and it is the site of involvement, as well as the type of inflammation, that defines the clinical presentation. Unlike ulcerative colitis, the inflammation in Crohn disease is transmural, and the bowel wall can become thickened, fibrotic, and strictured. The mucosal surface may develop cobblestoning related to edema with linear ulcerations. Deep fissures can develop and result in microperforations and the formation of fistulous tracts. The disease may be continuous but often has skip lesions with intervening segments of normal intestine. The mesentery can become infiltrated with fat, known as creeping fat. The disease is often present for months or years before diagnosis, and, in children, growth retardation may be the sole presenting sign. Distribution of Crohn disease is divided into three major patterns. The most common is ileocecal, which involves the distal portion of the small intestine (terminal ileum) and the proximal large bowel, and is observed in about 40% of patients. Ileocecal Crohn disease may mimic many other diseases, including acute appendicitis. Common symptoms include right lower quadrant abdominal pain, fever, weight loss, and sometimes a palpable inflammatory mass. Chronic inflammation, which leads to fibrosis and stricture formation, may result in partial or complete intestinal obstruction, as demonstrated by abdominal pain, distention, nausea, and vomiting. Because vitamin B12 and bile salts are absorbed in the terminal ileum, ileal Crohn disease or surgical resection of the terminal ileum may lead to B12 deficiency as well as deficiencies of the fat-soluble vitamins (A, D, E, and K) as a result of bile salt malabsorption.

The second major site of Crohn disease involves the small intestine, especially the terminal ileum, and is seen in about 30% of individuals at the time of presentation. Similar complications develop, including fistulas, which may form between different segments of bowel (e.g., enteroenteric, enterocolonic), bowel and skin (enterocutaneous), bowel and bladder (enterovesicular), and bowel and vagina (rectovaginal). The third site of disease is confined to the colon and is observed in 25% of individuals at the time of presentation. Although the disease often spares the rectum, 30% to 40% of patients may develop disabling perianal involvement with fissures, fistulas, and abscesses. Diarrhea is the major consequence but usually with less bleeding than that seen in ulcerative colitis. Distinguishing Crohn colitis from ulcerative colitis can be difficult. The remaining sites of Crohn disease are rare (5%) and include the esophagus, stomach, and duodenum.

MAJOR COMPLICATIONS Stenosis (Stricture) of the Small Intestine or Colon Stenosis may lead to bowel obstruction or stasis with subsequent small intestinal bacterial overgrowth.

Malabsorption Extensive ileal mucosal disease may lead to malabsorption of vitamin B12 (resulting in a megaloblastic anemia and neurologic side effects if not corrected) and malabsorption of bile salts (resulting in diarrhea induced by unabsorbed bile salts and potential fat-soluble vitamin deficiency). Depletion of the bile salt pool can lead to the formation of gallstones. Weight loss may result from generalized malabsorption caused by loss of absorptive surfaces.

Fistulas Transmural inflammation may lead to spontaneous drainage into adjacent bowel loops (enteroenteric fistula), bladder (enterovesical fistula), skin (enterocutaneous fistula), and vagina (rectovaginal), or it may lead to abscess formation around bowel or in other surrounding tissues.

Nephrolithiasis Chronic fat malabsorption leads to luminal binding of free fatty acids to calcium, allowing oxalate, which normally is poorly absorbed because it complexes to calcium in the gut lumen, to be absorbed. This increase in oxalate absorption increases the risk for urinary calcium oxalate stone formation. Patients with an ileostomy or chronic volume loss from diarrhea are also at increased risk for uric acid stones.

Malignancy For colonic Crohn disease, the risk for colorectal cancer is equivalent to ulcerative colitis of similar extent and duration. Therefore, screening and surveillance recommendations are similar to those for ulcerative colitis (see previous discussion). Patients with only small intestinal Crohn disease without colonic involvement are not thought to be at increased risk for colorectal cancer. The rates of small bowel carcinoma and lymphoma are increased in patients with Crohn disease.

Chapter 38—Inflammatory Bowel Disease

Diagnosis The diagnosis of IBD is based on a constellation of clinical features, laboratory tests, and endoscopic, radiographic, and histologic findings. Laboratory tests are not specific and usually reflect inflammation (leukocytosis) or anemia. Perinuclear antineutrophil cytoplasmic antibody (p-ANCA) is positive in up to 70% of patients with ulcerative colitis but rarely positive in patients with Crohn disease, whereas anti– Saccharomyces cerevisiae antibodies (ASCA) are common in Crohn disease and are rarely found in ulcerative colitis. Additional markers including anti–CBir-1 and anti–Omp-C may improve the sensitivity and specificity of serologic testing. Stool examination for ova and parasite identification and testing for Clostridium difficile toxin and enteric bacterial pathogens should be performed to exclude infections that can mimic IBD. Colonoscopy in patients with ulcerative colitis reveals a granular mucosa, decreased vascular markings, decreased mucosal reflection, and superficial ulcerations (Fig. 38-1). In more severe cases, the mucosa is friable, with deeper ulcerations and exudate. Patients with long-standing disease have pseudopolyps, which represent islands of normal tissue in regions of previous ulceration. On endoscopic examination in Crohn disease (Fig. 38-2), the involved mucosa may show aphthoid ulcerations, deep linear or stellate ulcers, edema, erythema, exudate, and friability with intervening areas of normal mucosa (skip lesions). In Crohn disease, small bowel radiography (i.e., small bowel follow-through) has traditionally been the best study with which to investigate the jejunum and ileum, although video capsule endoscopy has recently become increasingly used in this setting. Using this technology, small ulcerations and strictures that are undetectable on small bowel radiography can be visualized (Web Fig. 38-1), although patients

Figure 38-1 Endoscopic image in ulcerative colitis demonstrating diffuse inflammation characterized by erythema, edema, friability, and hemorrhage.

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with known or suspected strictures or fistulas should not undergo capsule endoscopy given the risk for capsule retention. On small bowel radiography, involved areas have edema and thickening of the bowel wall that lead to bowel loop separation and can also show ulcerations of the mucosa, fistulas, or strictures. A tight, long stricture in the small bowel is commonly called the string sign (Fig. 38-3). Linear ulcers with segments of edematous or uninvolved mucosa lead to the characteristic pattern referred to as cobblestoning. Computed tomographic (CT) scanning can often identify bowel wall thickening with surrounding inflammation as well as intra-abdominal abscesses and fistulas. The recent development of CT enterography and magnetic resonance enterography represent advances in small bowel imaging technology and will likely become primary imaging studies in patients with known or suspected Crohn disease. Mucosal biopsies in ulcerative colitis reveal crypt architectural distortion, with crypt abscesses and infiltration by plasma cells, neutrophils, lymphocytes, and eosinophils (Fig. 38-4). In Crohn disease, the inflammation is transmural and more commonly focal. Granulomas are found in 25% to 30% of histologic specimens in Crohn disease, but not in ulcerative colitis, and can assist in the diagnosis of Crohn disease in the right clinical setting (Fig. 38-5).

Differential Diagnosis The differential diagnosis of IBD includes infectious colitis, ischemic colitis, radiation enteritis, enterocolitis induced by nonsteroidal anti-inflammatory drugs, diverticulitis, appendicitis, gastrointestinal malignancies, and irritable bowel syndrome. In patients with acute onset of bloody diarrhea, infectious causes that must be excluded include Salmonella enteritidis, Shigella species, Campylobacter jejuni, Escherichia

Figure 38-2 Endoscopic image in Crohn disease demonstrating linear ulcers in areas of otherwise normal mucosa.

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Figure 38-4 Mucosal biopsy demonstrating crypt branching and a crypt abscess characteristic of ulcerative colitis (hematoxylin and eosin stain). (Courtesy of Niall Swan, MD.)

Figure 38-3 Radiograph demonstrating small bowel Crohn disease with skip areas and a string sign.

coli O157, and C. difficile. Among the infectious causes, Yersinia enterocolitica can mimic Crohn disease because the pathogen causes ileitis, mesenteric adenitis, fever, diarrhea, and right lower quadrant abdominal pain. Mycobacterium tuberculosis, strongyloidiasis, and amebiasis must be excluded in high-risk populations because these infections can mimic IBD, and treatment with corticosteroids can lead to disseminated infection and death.

Extraintestinal Manifestations Although both ulcerative colitis and Crohn disease primarily involve the bowel, they are associated with inflammatory manifestations in other organ systems, reflecting the systemic nature of these disorders (Table 38-1). Most of these manifestations occur frequently when the bowel is involved, and, in some cases, they may become more difficult to treat than the bowel disease itself. The most common extraintestinal manifestation is arthritis, of which two major types have been identified. The first is a peripheral, large joint, asymmetrical, seronegative, oligoarticular, nondeforming arthritis (about 20% of patients) that may involve the knees, hips, wrists, elbows, and ankles. This peripheral arthropathy usually parallels the course of the large bowel disease (colitic arthritis) and usually lasts for only

Figure 38-5 Colonic biopsy demonstrating chronic inflammatory infiltrate with a granuloma (hematoxylin and eosin stain; magnification 10×). (Courtesy of Niall Swan, MD.)

a few weeks. A second arthritis is axial in location, and its activity does not mirror that of the bowel disease. It consists of sacroiliitis or ankylosing spondylitis. Ankylosing spondylitis (about 5% to 10% of IBD patients) presents with low back pain and stiffness, usually worse during the night, in the morning, or after inactivity. Sacroiliitis alone (without ankylosing spondylitis) is common in IBD (up to about 80% of patients), but many of these patients are asymptomatic. Liver complications of IBD include both intrahepatic and biliary tract diseases. Intrahepatic diseases include fatty liver, pericholangitis, chronic active hepatitis, and cirrhosis. Pericholangitis, also known as small-duct sclerosing cholangitis, is the most common of these diseases and usually is asymptomatic, identified only by abnormalities in alkaline phosphatase and γ-glutamyl transpeptidase on laboratory tests and histologically by portal tract inflammation and bile ductule degeneration. Small-duct sclerosing cholangitis may progress to cirrhosis.

Chapter 38—Inflammatory Bowel Disease Table 38-1 Extraintestinal Manifestations of Inflammatory Bowel Disease Skin Pyoderma gangrenosum Erythema nodosum Sweet syndrome

Table 38-2 Differentiating Features Ulcerative Colitis

Musculoskeletal Seronegative arthritis Ankylosing spondylitis Sacroiliitis Ocular Uveitis Episcleritis

Only involves colon Rectum almost always involved

Pattern of involvement Diarrhea Severe abdominal pain Perianal disease Fistula Endoscopic findings

Continuous

Any area of the gastrointestinal tract Rectum usually spared Skip lesions

Bloody Rare

Usually nonbloody Frequent

No No Erythematous and friable Superficial ulceration Tubular appearance resulting from loss of haustral folds Mucosa only Crypt abscesses

In 30% of patients Yes Aphthoid and deep ulcers Cobblestoning

Miscellaneous Hypercoagulable state Autoimmune hemolytic anemia Amyloidosis

Biliary tract disease includes an increased incidence of gallstones and primary sclerosing cholangitis (PSC). PSC is a chronic cholestatic liver disease marked by fibrosis of the intrahepatic and extrahepatic bile ducts, occurring in 1% to 4% of patients with ulcerative colitis and less often in Crohn disease. Overall, about 70% of patients with PSC have ulcerative colitis. Fibrosis leads to strictures of the bile ducts, which, in turn, may lead to recurrent cholangitis (fever, right upper quadrant pain, and jaundice) and progression to cirrhosis. In addition, about 10% of patients develop cholangiocarcinoma. Medical or surgical therapy for the IBD does not modify the course of PSC, and most patients will pro gress to cirrhosis and liver failure over 5 to 10 years unless a liver transplantation is performed. The two classic dermatologic manifestations of IBD are pyoderma gangrenosum and erythema nodosum. Pyoderma gangrenosum (about 5% of patients) exhibits as a discrete ulcer with a necrotic base, usually on the legs. The ulcer may spread and become large and deep, destroying soft tissues. Pyoderma parallels the activity of the IBD in 50% of cases. Treatment is usually with systemic or intralesional steroids, or both. Other treatment options include dapsone, cyclosporine, and infliximab. Erythema nodosum (10% of patients, usually with peripheral arthropathy) exhibits raised, tender nodules, usually over the anterior surface of the tibia. It heals without scarring and responds to treatment for the underlying bowel disease. A less common dermatologic manifestation of IBD is Sweet syndrome, or acute febrile neutrophilic dermatosis. This is a condition characterized by the sudden onset of fever, leukocytosis, and tender, erythematous, welldemarcated papules and plaques that show dense neutrophilic infiltrates on histologic examination. Ocular manifestations of IBD include uveitis and episcleritis (5%). Uveitis (or iritis) is an inflammatory lesion of the anterior chamber and produces blurred vision, photophobia, headache, and conjunctival injection. Local therapy includes steroids and atropine. Episcleritis is less serious

Crohn Disease

Site of involvement

Hepatobiliary Primary sclerosing cholangitis Cholelithiasis Autoimmune hepatitis

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Radiologic findings

Histologic features Smoking Serology

Protective p-ANCA more common

String sign of terminal ileum RLQ mass, fistulas, abscesses Transmural Crypt abscesses, granulomas (about 30%) Worsens course ASCA more common

ASCA, anti–Saccharomyces cerevisiae antibodies; p-ANCA, perinuclear antineutrophil cytoplasmic antibody; RLQ, right lower quadrant.

than uveitis, producing burning eyes and scleral injection, and is treated with topical steroids. Other complications of IBD include chronic anemia (common), digital clubbing and hypertrophic osteoarthropathy (uncommon in adults), an increased incidence of thromboembolic disease (uncommon), and amyloidosis (rare).

Differentiation between Ulcerative Colitis and Crohn Disease Generally, the diagnoses of ulcerative colitis and Crohn disease can be made based on the findings as described in their respective sections presented earlier and those outlined in Table 38-2. As noted, most Crohn patients have small bowel involvement, skip lesions, and pain, whereas most ulcerative colitis patients have bloody diarrhea with involvement of the rectum and a continuous, superficial spread of the disease. The endoscopic, radiologic, and histologic criteria aid in the phenotypic differentiation of these disease entities. However, occasionally, a diagnosis of indeterminate colitis is made as a result of an overlap of findings. For example, colonic Crohn disease may produce superficial continuous rectal involvement similar to ulcerative proctitis. Similarly, chronic ulcerative colitis can infrequently result in

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inflammation of the terminal ileum, called backwash ileitis. In many indeterminate cases, repeated examination is necessary, or complications develop that help identify the form of the disease.

Treatment (Induction and Maintenance of Remission) As part of the initial management of patients with IBD, the clinician must determine the extent and assess the severity of the disease. Patients with mild or moderate disease can be managed as outpatients with close monitoring in association with a gastroenterologist. Patients with severe or fulminant disease, as indicated by abdominal pain, fever, tachycardia, anemia, and leukocytosis, require hospital admission and multidisciplinary team management. Because IBD is a chronic recurrent illness, treatment is centered on controlling the acute attack with induction of remission followed by maintenance of remission. Treatment options for ulcerative colitis and Crohn disease are reviewed in Table 38-3.

5-AMINOSALICYLIC ACID The aminosalicylates are given either orally or topically (suppository and enema) and are safe and effective in the treatment of mild to moderate disease as well as in maintenance of remission of ulcerative colitis. The efficacy of most of these agents in the induction or maintenance of remission of Crohn disease is questionable. This category includes sulfasalazine (Azulfidine) at a dose of 4 to 6 g/day in divided doses, which consists of 5-aminosalicylic acid (5-ASA) linked to a sulfapyridine moiety and which is activated following the release of the 5-ASA after bacterial lysis in the colon. Side effects, including headache, nausea, and skin

Table 38-3 Treatment Options Disease Severity

Ulcerative Colitis

Mild

Oral and topical 5-ASA compounds Oral and topical 5-ASA compounds Oral steroids Azathioprine, 6-MP Infliximab

Moderate

Severe

Intravenous steroids Cyclosporine Infliximab Surgery

Crohn Disease 5-ASA compounds Antibiotics Elemental diet 5-ASA compounds Antibiotics Budesonide or oral steroids Azathioprine, 6-MP Methotrexate Infliximab, adalimumab, certolizumab, natalizumab Intravenous steroids Azathioprine, 6-MP Methotrexate Infliximab, adalimumab, certolizumab, natalizumab Surgery

5-ASA, 5-aminosalicylic acid; 6-MP, 6-mercaptopurine.

reactions, may require discontinuation of sulfasalazine in about 30% of patients. Reversible oligospermia may occur with sulfasalazine, and rare serious side effects include pleuropericarditis, pancreatitis, agranulocytosis, interstitial nephritis, and hemolytic anemia. Patients who take sulfasalazine need folic acid supplementation. Newer derivatives of oral 5-ASA compounds, such as mesalamine (Pentasa, 4 g per day in divided doses; Asacol, 2.4 g per day in divided doses; Lialda, 2.4 to 4.8 g once daily), olsalazine (Dipentum, 1 to 2 g per day in divided doses), and balsalazide (Colazal, 6.75 g per day in divided doses), as well as topical forms of mesalamine (Canasa suppositories, 1000 mg once daily; or Rowasa enemas, 4 g once nightly), are being commonly used because of a favorable side-effect profile. In addition to their use in the primary treatment of IBD, several studies suggest that long-term use of 5-ASA medications may reduce the risk for colorectal cancer in patients with ulcerative colitis.

CORTICOSTEROIDS Corticosteroids may be used topically, orally, or intravenously and are effective for controlling active disease but are not useful for maintaining remission. They are indicated for moderate or severe disease and in patients in whom treatment with 5-ASA fails. The most commonly used agent is prednisone, started in doses between 40 and 60 mg per day. Patients typically improve rapidly, and the medication is usually tapered down slowly, that is, 5 to 10 mg per week until discontinuation. Patients who do not improve after 1 week of oral treatment and those with more severe disease are best treated in the hospital with intravenous corticosteroids, such as intravenous hydrocortisone, 300 mg per day, or methylprednisolone, which can be given either by continuous infusion or in three divided doses. Corticosteroids have numerous side effects with long-term use. Budesonide (Entocort, 9 mg given once daily), a corticosteroid that undergoes extensive first-pass hepatic metabolism, is now available for inducing and maintaining remission of ileocolonic Crohn disease and may offer long-term benefits with decreased corticosteroid side effects. Controlled trials have shown that budesonide is more effective than placebo and oral 5-ASA, and has similar efficacy to prednisolone for the induction of remission in Crohn disease.

ANTIBIOTICS Antibiotics are primarily used in patients with Crohn disease who have colonic, perianal, or fistulizing disease. Intravenous antibiotics are also part of the initial treatment in patients with severe, toxic, or fulminant colitis. The two commonly used antibiotics are metronidazole (Flagyl) and ciprofloxacin (Cipro). Ciprofloxacin is prescribed at a dosage of 500 mg twice a day. Metronidazole is prescribed at a dosage of 20 mg/kg per day in three divided doses. Patients should be warned of potential side effects, such as a disulfiram (Antabuse) effect and peripheral neuropathy.

IMMUNOMODULATORS Included in this category are azathioprine (Imuran, 2 to 2.5 mg/kg per day) and its active metabolite 6-

Chapter 38—Inflammatory Bowel Disease mercaptopurine (6-MP) (Purinethol, 1 to 1.5 mg/kg per day) as well as methotrexate and cyclosporine. Azathioprine and 6-MP are effective therapies for maintaining remission in both Crohn disease and ulcerative colitis and are used primarily as steroid-sparing agents. They have a slow onset of action (months) but are generally safe and well tolerated. Other regimens include subcutaneous or intramuscular methotrexate for induction (25 mg weekly) and maintenance of remission (15 to 25 mg weekly) in active Crohn disease and intravenous cyclosporine (2 to 4 mg/kg per day given over 24 hours) as bridge treatment for severe steroidrefractory ulcerative colitis. Given the potential for both short-term and long-term side effects, as well as the need for close follow-up, patients needing these medications are best managed by gastroenterologists.

BIOLOGIC THERAPY Advances in our knowledge of the immunopathogenesis of IBD have led to a new class of therapies that target specific aspects of the immune system, collectively known as the biologic agents. The first such agent to be used in IBD was infliximab, a chimeric monoclonal antibody to TNF-α, which has been shown to be effective in the treatment of moderate to severe Crohn disease, including fistulizing disease. More recently, infliximab has also been shown to be beneficial in the treatment of ulcerative colitis that is refractory to conventional medical therapy. Because infliximab is a chimeric antibody, its toxicities include infusion reactions, delayed-type hypersensitivity reactions, and formation of autoantibodies (which can reduce its efficacy). Two newer anti-TNF agents, adalimumab (a fully human monoclonal antibody), and certolizumab pegol (a humanized anti-TNF antibody Fab fragment), have also proved efficacious in patients with moderate to severe Crohn disease who have not responded well to conventional treatments. These two agents are administered subcutaneously, and may have a lower toxicity profile. Natalizumab, a humanized anti–α4integrin antibody, blocks inflammatory cell migration and adhesion and has recently been approved for the treatment of moderate to severe Crohn disease in patients who have had an inadequate response to, or are unable to tolerate, conventional Crohn disease therapies including inhibitors of TNF-α. Because of the potent effects these biologic agents have on the immune system, careful patient selection and monitoring for complications are necessary. Reactivation of latent tuberculosis and other serious infections have been reported with the anti-TNF agents, and there may be an increased risk for non-Hodgkin lymphoma and possibly solid tumors as well. Natalizumab has been linked to rare cases of progressive multifocal leukoencephalopathy caused by the human polyoma JC virus.

PROBIOTICS Probiotics are viable nonpathogenic organisms that, after ingestion, may prevent or treat intestinal diseases. Probiotics are being explored in treatment of IBD and may help prevent recurrence after surgery for Crohn disease and to treat pouchitis after ileal pouch-anal anastomosis.

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NUTRITIONAL SUPPORT Nutritional support is an important adjunctive aspect in the management of patients with IBD. However, the role of nutrition as a primary treatment has been limited to patients with small bowel Crohn disease. These patients may achieve and maintain remission with total parenteral nutrition or elemental diets after prolonged periods (at least 4 weeks). Many patients with Crohn disease and ulcerative colitis experience weight loss during exacerbations of their illness and need caloric supplements. Vitamins and minerals can be given orally as a multivitamin with folic acid. Vitamin B12 should be supplemented parenterally in patients who have extensive ileal disease or an ileal resection. Patients taking corticosteroids require supplemental calcium and vitamin D, and individuals with extensive small bowel involvement can also develop malabsorption of fat-soluble vitamins (A, D, E, and K), iron deficiency, and rarely trace minerals. Lactose-free diets, as well as low-fiber diets, may be necessary in patients with active disease or strictures.

ANTIDIARRHEALS AND BILE SALT RESIN BINDERS Antidiarrheal agents and bile salt resin binders are adjuncts used to manage diarrhea in patients with IBD. Antidiarrheal agents should be used cautiously during exacerbations of colitis because they can precipitate toxic megacolon. The main role of these medications involves controlling diarrhea in patients who have undergone previous resections. Generally, when less than 100 cm of terminal ileum has been resected, patients can develop a bile salt malabsorptive state during which bile salts enter the colon and result in a secretory diarrhea. Bile salt resin binders such as cholestyramine are an effective treatment in these cases. When patients have undergone one or more extensive resections, the bile salt pool is depleted, and fat malabsorption develops. These patients may require a low-fat diet supplemented with medium-chain triglycerides and antidiarrheal agents, but bile salt resin binders should not be used.

SURGICAL MANAGEMENT Surgical intervention is indicated for patients with severe complications such as obstruction, perforation, massive gastrointestinal hemorrhage, and toxic megacolon not responsive to medical treatment. The other main indication for surgical treatment is the presence of dysplasia or cancer. For patients with ulcerative colitis, regardless of the extent of disease, the entire colon must be removed, and the operation is essentially curative. About 20% to 25% of patients have pancolitis, and one third to one half will require colectomy within 2 to 5 years of diagnosis, depending on the severity of their colitis. In contrast, less than 10% of individuals with mild disease or proctitis will undergo colectomy by 10 years after diagnosis. Historically, the initial operation for ulcerative colitis was a total proctocolectomy and Brooke ileostomy. More recently, the ileal pouch-anal anastomosis has become the operation of choice in most patients. In this operation, the colon is removed, and the small bowel is constructed into a reservoir (ileal pouch) that

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is anastomosed to the anus, allowing defecation through the anus. Complications of this operation include the development of pouchitis, fecal incontinence, reduced fertility, and need for reoperation. Surgery is not curative in Crohn disease and is generally avoided, if possible. Nonetheless, 10 years after a diagnosis of Crohn disease, more than 60% of patients will require

surgery. Many surgical procedures in patients with Crohn disease are performed to manage complications of the disease, including segmental resection, stricturoplasty, fistulectomy, and abscess drainage. Unfortunately, the recurrence rate is high, with 70% of patients having an endoscopic recurrence within 1 year of surgery and 50% having a symptomatic recurrence within 4 years.

Prospectus for the Future As our understanding of the etiologic and pathophysiologic aspects of inflammatory bowel disease increases, major advancements in diagnosis and treatment are anticipated. These advancements include the following: • The use of molecular, genetic, and serologic tests to differentiate between subtypes of disease as well as identify individuals at high risk for developing complications of inflammatory bowel disease

References Baumgart DC, Sandborn WJ: Inflammatory bowel disease: Clinical aspects and established and evolving therapies. Lancet 369:1641, 2007. Brown SJ, Mayer L: The immune response in inflammatory bowel disease. Am J Gastroenterol 102:2058, 2007. Cho JH: The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol 8:458, 2008. Cima RR, Pemberton JH: Medical and surgical management of chronic ulcerative colitis. Arch Surg 140:300, 2005. D’Haens G, Baert F, van Assche G, et al: Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: An open randomised trial. Lancet 371:660-667, 2008. Itzkowitz SH, Present DH: Crohn’s and Colitis Foundation of America, Colon Cancer in IBD Study Group: Consensus Conference. Colorectal cancer

• The increased, and earlier, use of biologic agents to specifically target aspects of the immune system and inflammatory pathways known to be involved in IBD pathophysiology • Improvements in the detection of dysplasia and prevention of colorectal cancer (including chemoprevention) in patients with chronic colitis

screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 11:314, 2005. Katz S: Update in medical therapy of ulcerative colitis: Newer concepts and therapies. J Clin Gastroenterol 39:557, 2005. Kornbluth A, Sachar DB: Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 99:1371, 2004. Peyrin-Biroulet L, Desreumaux P, Sandborn WJ, Colombel JF: Crohn’s disease: Beyond antagonists of tumour necrosis factor. Lancet 372:67-81, 2008. Sandborn WJ, Feagan BG, Lichtenstein GR: Medical management of mild to moderate Crohn’s disease: Evidence-based treatment algorithms for induction and maintenance of remission. Aliment Pharmacol Ther 26:987-1003, 2007. Siegel CA, Sands BE: Review article: Practical management of inflammatory bowel disease patients taking immunomodulators. Aliment Pharmacol Ther 22:1, 2005.

Chapter

39

VII

Neoplasms of the Gastrointestinal Tract Paul C. Schroy III

Esophageal Carcinoma Carcinoma of the esophagus is one of the most lethal of all cancers. The lack of early symptoms and serosal barrier, as well as the rich, bidirectional esophageal lymphatic flow, often results in advanced disease by the time of diagnosis. The American Cancer Society estimates that about 16,500 new cases of esophageal cancer and 14,530 esophageal cancer deaths will occur in the United States in 2009. Historically, squamous cell carcinoma (SCC) constituted 95% of all esophageal carcinomas. Since 1980, however, the incidence of adenocarcinoma of the esophagus has rapidly increased and now accounts for about 50% of newly diagnosed cases of esophageal carcinoma. The epidemiology of SCC differs from that of adenocarcinoma of the esophagus, but the symptoms, treatments, and prognoses are similar.

INCIDENCE AND EPIDEMIOLOGY The incidence of SCC varies dramatically throughout the world. The highest rates are found in developing countries such as northern China, Iran, India, and parts of southern Africa. SCC is relatively uncommon in the United States, with an annual incidence of less than 5 cases per 100,000 population. Esophageal cancer is rare among individuals younger than 40 years, but thereafter increases in incidence with each subsequent decade. Men are affected more often than women, and African Americans have a fivefold increase in incidence compared with other racial and ethnic groups. The cause of SCC is unknown, but environmental, dietary, and local esophageal factors have been implicated. Heavy alcohol consumption and smoking are the predominant risk factors for SCC in the United States. In developing countries, nutritional deficiencies (e.g., selenium), betel nut chewing, human papillomavirus infection, and consumption of extremely hot drinks (e.g., tea), nitrates, and pickled vegetables, are also important risk factors. Predisposing conditions include lye strictures, radiation injury, Plummer-Vinson syndrome, achalasia, tylosis, and celiac disease.

Adenocarcinoma of the esophagus is primarily a disease of white men. The primary risk factor for adenocarcinoma is Barrett esophagus, a condition in which specialized intestinal-type columnar mucosa replaces the normal squamous mucosa in response to chronic gastroesophageal reflux disease. It is presumed that intestinal metaplasia progresses to low-grade dysplasia and then high-grade dysplasia and finally adenocarcinoma. The risk for developing adenocarcinoma in the setting of Barrett esophagus is about 0.5% per year. Long-standing gastroesophageal disease, obesity, and cigarette smoking have also been implicated as potential causative factors. Endoscopic surveillance with biopsy is recommended for Barrett esophagus but not chronic gastroesophageal reflux disease.

Clinical Presentation Early and curable esophageal carcinoma is frequently asymptomatic and detected serendipitously. The presence of symptoms heralds an advanced and most often incurable stage of disease. Under careful questioning, most patients will have had symptoms for a few months before seeking medical attention. Dysphagia is the most common symptom of esophageal carcinoma. It occurs when the esophageal lumen has been compromised by about 75% of its normal diameter. Difficulty swallowing solid foods precedes dysphagia to liquids. With complete obstruction, regurgitation, aspiration, and cough or pneumonia may occur. Pulmonary symptoms may also occur if a tracheoesophageal fistula is present. Patients uniformly have weight loss and anorexia. Chest pain, hiccups, or hoarseness indicates involvement of adjacent structures such as the mediastinum, diaphragm, and recurrent laryngeal nerve, respectively. If gastrointestinal bleeding occurs, it is often occult or associated with iron deficiency anemia. Life-threatening gastrointestinal hemorrhage can occur if the tumor has invaded major vessels. Clubbing of the nails and paraneoplastic syndromes, such as hypercalcemia and Cushing syndrome, are rarely seen. 439

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Section VII—Gastrointestinal Disease H. pylori

DIAGNOSIS Patients with dysphagia or other suggestive symptoms should be evaluated by upper endoscopy or an esophageal barium study. The advantage of endoscopy includes the opportunity to obtain tissue of the cancer, either by biopsy or brush cytologic study. Esophageal carcinoma may appear as a plaque, an ulcer, a stricture, or a mass. Nearly 90% of adenocarcinomas develop in the distal esophagus, whereas 50% of SCCs occur in the middle third of the esophagus, and the other 50% are evenly distributed in the proximal and distal esophagus. Computed tomography (CT) scanning of the chest and abdomen is performed to detect invasion of local structures and metastases to the lung and liver. Endoscopic ultrasonography (EUS), with its ability to image the esophageal wall as a five-layer structure that correlates with histologic layers, is more accurate than CT for staging tumor depth, local invasion, and regional node involvement. EUS also permits targeted fine-needle aspiration of suspicious findings.

THERAPY Stage is the most important prognostic factor for the survival of patients with esophageal cancer and influences the treatment options. Staging is based on the tumor-node-metastasis (TNM) classification system. Only localized tumors confined to the wall of the esophagus are potentially curable by surgery. Overall 5-year survival rates for patients undergoing curative resection, however, are just 5% to 20%. Preoperative chemotherapy with multidrug regimens combined with radiation therapy may reduce local recurrence rates and improve survival. Chemotherapy plus radiation therapy is also recommended for patients with locally unresectable disease, medical conditions that preclude surgery, and those who refuse surgery. Patients with metastatic disease should be considered for palliative treatment of dysphagia. Local treatment with endoscopic methods (such as malignant stricture dilation), placement of an endoprosthesis (stent), and tumor ablation by laser or photodynamic therapy are often the methods of choice for rapid palliation. More sustained palliation can be achieved using combined chemotherapy and radiation therapy.

Gastric Carcinoma Gastric carcinoma is one of the leading causes of cancerrelated deaths worldwide. For unknown reasons, the incidence of gastric cancer has declined dramatically in the United States since the 1930s. Despite its declining incidence, the American Cancer Society estimates that about 21,100 new cases and 10,620 gastric cancer deaths will occur in 2009. Unfortunately, gastric cancer is often advanced at the time of diagnosis; the 5-year survival rate is about 24%.

INCIDENCE AND EPIDEMIOLOGY More than 90% of gastric cancers are adenocarcinomas. The incidence of gastric cancer varies widely throughout the world. The disease is more common in developing countries than industrialized nations and shows a predilection for

Dietary factors

Chronic active gastritis

Host factors

Intestinal metaplasia

Dysplasia

ADENOCARCINOMA Figure 39-1 Model for the development of gastric adenocarcinoma.

urban and lower socioeconomic groups. Japan, China, the Andean regions of South America, and Eastern Europe exhibit the highest rates. The United States has among the lowest incidence rates at less than 10 cases per 100,000 population. Gastric cancer rarely occurs before age 40 years; thereafter, the incidence rises steadily, peaking in the seventh decade. Men are afflicted at a rate nearly twice that of women. African Americans, Hispanic Americans, and Native Americans are 1.5 to 2.5 times more likely to develop gastric cancer than whites. Migrants typically acquire the risk of their host countries, suggesting an important role for environmental factors. Low socioeconomic status, improper food storage, and other dietary and local gastric factors are associated with the disease. Dietary factors include deficiencies in fats, protein, and vitamins A and C and excesses in salted meat and fish, smoked foods, pickled vegetables, and nitrates. Predisposing conditions including atrophic gastritis, postgastrectomy states, achlorhydria, pernicious anemia, adenomatous polyps, and Ménétrier disease are also associated with an increased incidence. The World Health Organization has classified Helicobacter pylori as a carcinogen and epidemiologically linked to gastric adenocarcinoma (Fig. 39-1). However, only a small proportion of patients infected with H. pylori develop gastric adenocarcinoma. Gastric lymphomas account for fewer than 5% of primary gastric malignancies. The stomach is the most common site of extranodal non-Hodgkin lymphoma, but Hodgkin lymphoma of the stomach is rare. Gastric mucosa-associated lymphoid tissue (MALT) lymphomas are associated with H. pylori infection in 90% of cases and are reported to regress in 60% to 70% of cases after eradication of H. pylori. MALT lymphomas can also occur in association with various autoimmune and immunodeficiency syndromes. Most develop in individuals older than 50 years, and there is a slight male predominance.

CLINICAL PRESENTATION The location, size, and growth pattern of gastric malignancies may influence the presenting symptoms. Abdominal discomfort is the most frequent symptom; however, early satiety, nausea, and vomiting may occur, especially with gastric outlet obstruction. Gastrointestinal bleeding may manifest as iron deficiency anemia, occult bleeding, or

Chapter 39—Neoplasms of the Gastrointestinal Tract frank upper gastrointestinal hemorrhage. Anorexia and weight loss often accompany other symptoms. The signs of metastatic disease, which may be found on physical examination and signify incurability, include a Virchow (left supraclavicular) node, a Blumer shelf (mass in the perirectal pouch, found on digital rectal examination), and a Krukenberg tumor (metastasis to the ovaries). A variety of paraneoplastic syndromes have been associated with gastric adenocarcinoma and warrant an investigation for a gastrointestinal malignancy. They include Trousseau syndrome (thrombosis), acanthosis nigricans (pigmented dermal lesions), membranous nephropathy, microangiopathic hemolytic anemia, Leser-Trélat sign (seborrheic keratoses), and dermatomyositis.

DIAGNOSIS The diagnostic tests for gastric malignancies include double contrast (barium) upper gastrointestinal radiography or endoscopy. Lesions detected on barium study require endoscopic biopsy and cytologic study for histologic evaluation. Gastric carcinomas may appear as ulcers, masses, enlarged gastric folds, or an infiltrative process with a nondistensible stomach wall (linitis plastica). The accuracy of endoscopic ultrasonography is in the range of 77% to 93% for determining the depth of invasion and 65% to 90% for predicting regional node involvement. CT scanning of the chest and abdomen may detect metastases in the lung and liver but is otherwise poor for staging. Laparoscopy is increasingly being used for staging and determination of resectability with high accuracy.

THERAPY The standard treatment of gastric cancer is complete surgical resection with removal of all gross and microscopic disease. The postoperative local-regional recurrence rate remains 80%. A postoperative combination of chemotherapy plus radiation therapy reduces local recurrence rates and improves survival in patients undergoing curative resection. In the United States, nearly two thirds of patients present with advanced disease (stages III to IV), with a survival rate of less than 20%. Chemotherapy is the mainstay of treatment for such patients, but long-term survival is rare. Palliative resection may be performed to prevent obstruction or treat bleeding; radiation therapy and endoscopy may also be of palliative benefit in select patients. Treatment options for gastric lymphomas include some combination of chemotherapy, radiation therapy, and surgery, depending on stage of disease.

Colorectal Polyps and Carcinoma Carcinoma of the colon and rectum is the third most common cancer and the second most common cause of cancer deaths in American men and women. More than 146,970 new cases and 49,920 colorectal cancer-related deaths will occur in 2009. Screening has been shown to be an effective strategy for reducing both colorectal cancer mortality, through early detection, and incidence, through the identification and removal of premalignant adenomas.

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INCIDENCE AND EPIDEMIOLOGY Worldwide incidence and mortality of colorectal cancer varies considerably. With the notable exception of Japan, industrialized countries are at greatest risk. In the United States, incidence rates have declined slightly during the past decade but remain in excess of 40 cases per 100,000 persons. About 6% of Americans will develop colorectal cancer during their lifetime. Age is an important determinant of risk. Although extremely uncommon in individuals younger than 35 years (except those with rare predisposing genetic syndromes), the incidence of colorectal cancer increases steadily with age, beginning at about 40 years of age, with an approximate doubling with each successive decade thereafter to about 80 years of age. Cancer of the colon affects men and women at similar rates, whereas cancer of the rectum is more common in men. Colorectal cancer does not appear to have a racial predilection; however, African Americans are more likely to present with advanced-stage disease. Epidemiologic studies have identified a number of modifiable risk factors related to colorectal cancer. Factors associated with an increased risk for the disease include obesity, red meat, alcohol, and tobacco; conversely, factors associated with a decreased risk include physical activity, nonsteroidal antiinflammatory agents, and multivitamins. Most colorectal cancers are believed to arise from benign adenomatous polyps (adenomas). The epidemiology of colorectal adenomas is similar to that of colorectal cancer. In general, the prevalence of colorectal adenomas in a given country parallels the prevalence of colorectal cancer. Age is an important determinant of prevalence in high-risk countries. In the United States, autopsy studies suggest an overall prevalence of 50%, ranging from about 30% at age 50 years to 55% at age 80 years. Fortunately, only a minority of adenomas progress to colorectal cancer. It is unknown how long an adenoma takes to develop into an invasive cancer, but data from multiple observational studies suggest at least 10 years. Insight into the molecular mechanisms responsible for the adenoma-carcinoma sequence suggests that colorectal carcinogenesis is a multistage process (Fig. 39-2) resulting from the accumulation of genetic alterations involving various oncogenes (e.g., K-ras), tumor suppressor genes (e.g., APC or β-catenin, DCC, SMAD-4, SMAD-2, and p53), or DNA mismatch repair genes (e.g., hMLH-1). High-risk groups have been identified and include those with a personal or family history of colorectal cancer or adenomas, various genetic polyposis and nonpolyposis syndromes, and inflammatory bowel disease (Table 39-1). Hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) are well-defined genetic syndromes associated with the highest risk for colorectal cancer. HNPCC (Lynch syndromes) is characterized by inherited mutations in one of the DNA mismatch repair genes (e.g., hMLH-1 or hMSH-2), early-onset colorectal cancer (average age, 44 years) in the absence of polyposis, a predominance (60% to 70%) of tumors proximal to the splenic flexure, an excess of both colorectal and extracolonic (e.g., endometrial) cancers, and an estimated lifetime risk for colorectal cancer of 80% to 90%. In contrast, FAP is characterized by inherited mutations in the APC gene, the appearance of hundreds of colorectal adenomas during the second or third decade of life, and a risk for colorectal cancer

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Section VII—Gastrointestinal Disease DNA hypomethylation

Chromosome alteration gene

12p mutation K-ras

5q mutation or loss APC/b-catenin

Normal epithelium

Hyperproliferative epithelium

Other alterations

Early adenoma

18q loss DCC/SMAD-2/SMAD-4

Intermediate adenoma

Late adenoma

17p loss p53

Carcinoma

Metastasis

DNA Mismatch Repair (MMR) gene inactivation (e.g., MLH-1 hypermethylation) Figure 39-2 A genetic model for colorectal tumorigenesis.

Table 39-1 Risk Factors for Colorectal Cancer Age ≥ 50 yr Personal history of adenomatous polyps or colorectal cancer Familial adenomatous polyposis or Gardner syndrome MYH-associated adenomatous polyposis Hereditary nonpolyposis colon cancer Ulcerative colitis or Crohn colitis First-degree relative with colon cancer or adenomatous polyps diagnosed before age 60 yr Hamartomatous polyposis syndrome (Peutz-Jeghers syndrome, juvenile polyposis)

that approaches 100% by the fifth decade if left untreated. FAP is also associated with benign fundic gland polyps in the stomach and duodenal adenomas and adenocarcinomas that have a predilection for the periampullary region. Gardner syndrome is a variant of FAP in which affected probands also exhibit a variety of extraintestinal manifestations such as osteomas, desmoids, and other soft tissue tumors. Congenital hypertrophy of the retinal pigment epithelium is an early benign manifestation of both FAP and Gardner syndrome. MYH-associated adenomatous polyposis syndrome is indistinguishable from FAP clinically but caused by mutations of the base excision repair gene, mutY homologue (MYH) rather than APC. Peutz-Jeghers syndrome is an autosomal dominant condition characterized by hamartomatous polyposis of both the small and large bowel and mucocutaneous pigmentation. Affected individuals are at increased risk for both gastrointestinal (stomach, small bowel, and colon) and extraintestinal (e.g., genital tract, pancreas, and breast) malignancies occurring at a young age. Generalized juvenile polyposis is another inherited hamartomatous polyposis syndrome associated with a small, albeit increased, risk for colorectal cancer.

CLINICAL PRESENTATION Most colorectal neoplasms are asymptomatic until advanced. Gastrointestinal blood loss is the most common symptom

and may present as occult bleeding, hematochezia, or unexplained iron deficiency anemia. Other symptoms include abdominal pain from obstruction or invasion, change in bowel habits, or unexplained anorexia or weight loss. A palpable mass may be present in patients with advanced cancers of the cecum.

DIAGNOSIS All patients with symptoms suggestive of colorectal neoplasia should undergo an evaluation of the colon by colonoscopy, flexible sigmoidoscopy, or double contrast barium enema. About 50% of colorectal adenomas and cancers are located between the rectum and splenic flexure; however, the prevalence of cancers proximal to the splenic flexure increases with increasing age, especially among women. Colorectal cancers may arise in sessile (flat) or pedunculated (on a stalk) polyps, or they may appear as a stricture, a fungating mass, or an ulcerated mass. Colonoscopy has greater accuracy than a barium enema study in the detection of small polyps and early cancers as well as the ability to remove neoplasms or biopsy lesions at the time of the examination. Lesions detected on barium enema study necessitate colonoscopic evaluation. CT scanning and of the abdomen and pelvis is used preoperatively to assess the extent of metastatic disease. Magnetic resonance scanning and positron emission tomography may also be useful in detecting metastatic disease in select patients. EUS is used for the preoperative staging of rectal cancer. Carcinoembryonic antigen level is measured preoperatively for a baseline value and, if elevated, monitored to detect tumor recurrence postoperatively. Periodic screening by colonoscopy, CT colonography (virtual colonoscopy), flexible sigmoidoscopy, or doublecontrast enema is recommended for asymptomatic, averagerisk patients beginning at age 50 years. Stool blood testing and stool DNA testing are alternative screening methods for patients who refuse one of the preferred methods (Table 39-2). Screening recommendations for high-risk patients vary depending on the risk factor (see Table 39-2) but in general rely on colonoscopy performed at a younger age and at more frequent intervals than for those at average risk.

Chapter 39—Neoplasms of the Gastrointestinal Tract

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Table 39-2 Colorectal Cancer (CRC) Screening and Surveillance Recommendations* Indication

Recommendations

Average risk

Beginning at age 50 yr: Colonoscopy every 10 yr Computed tomographic colonography every 5 yr Flexible sigmoidoscopy every 5 yr Double-contrast barium enema every 5 yr (Stool blood testing annually or stool DNA testing acceptable but not preferred) Colonoscopy every 5 yr beginning at age 40 yr, or 10 yr younger than earliest diagnosis, whichever comes first Genetic counseling and screening† Colonoscopy every 1 to 2 years beginning at age 25 yr and then yearly after age 40 yr‡ Genetic counseling and testing† Flexible sigmoidoscopy yearly beginning at puberty‡ Colonoscopy within 1 yr of curative resection; repeat at 3 yr and then every 5 yr if normal Colonoscopy every 3 to 5 yr after removal of all index polyps Colonoscopy every 1 to 2 yr beginning after 8 yr of pancolitis or after 15 yr if only left-sided disease

One or two first-degree relatives with CRC at any age or adenoma at age < 60 yr Hereditary nonpolyposis colorectal cancer

Familial adenomatous polyposis and variants Personal history of CRC Personal history of colorectal adenoma Inflammatory bowel disease

*Recommendations proposed by the American Cancer Society and U.S. Multi-Society Task Force on Colorectal Cancer; recommendations for averagerisk patients also endorsed by the American College of Radiology. † Whenever possible, affected relatives should be tested first because of potential false-negative results. ‡ Screening recommendation for individuals with positive or indeterminate tests as well as for those who refuse genetic testing.

Colonoscopic surveillance is recommended for patients with a history of colorectal cancer or adenomas and inflammatory bowel disease.

THERAPY The rate of survival of patients with colorectal carcinoma is based on the stage of disease (Table 39-3). Unfortunately, 45% of patients first come to medical attention with stage III or IV disease. Surgery alone is curative for early-stage colorectal cancers. Surgery and adjuvant chemotherapy with 5-fluorouracil and leucovorin ± oxiliplatin or capecitabine alone are recommended for stage III colon cancer. For patients with stage II and III rectal cancer, the combination of postoperative radiation and 5-fluorouracil (± leucovorin) has been found to significantly reduce the recurrence rate, cancer-related deaths, and overall mortality. Independent of nodal status, preoperative chemoradiotherapy followed adjuvant chemotherapy is recommended for patients with locally advanced rectal cancers. For patients with stage IV disease, palliative surgery, chemotherapy, and radiation therapy are the mainstays of therapy.

Carcinoid Tumors The overall incidence of gastrointestinal carcinoid tumors in the United States is estimated at 1 to 2 cases per 100,000 people. The most common sites, in descending order of frequency, are the small intestine (ileum), rectum, appendix, colon, and stomach. Carcinoid tumors arise from neuroendocrine cells and contain a variety of secretory granules containing various hormones and biogenic amines. Serotonin is synthesized

Table 39-3 Survival and Comparison of Dukes and TNM Staging in Colorectal Carcinoma Dukes A B C D

TNM Stage

5-Year Survival Rate (%)

I II III IV

93 72-85 44-83 8

from 5-hydroxytryptophan and metabolized in the liver to 5-hydroxyindoleacetic acid, which is biologically inert and secreted in the urine. The release of serotonin (hindgut tumors) and other vasoactive substances into the systemic circulation is thought to cause the carcinoid syndrome. Therefore, carcinoid metastases in the liver or other sites that drain into systemic veins may be associated with the carcinoid syndrome, as may primary carcinoids in the ovary or bronchus. The symptoms include episodic flushing, wheezing, diarrhea, right-sided valvular heart disease, and, potentially, vasomotor collapse. Localized tumors may present with gross or occult bleeding, obstructive symptoms, or abdominal pain depending on their location. Most carcinoids are indolent; however, the malignant potential is variable and appears to be related to the site and, often, the size of the primary tumor. Carcinoids arising in the ileum and those 2 cm or larger have the greatest malignant potential. Surgical resection is the only curative treatment for carcinoid tumors. Somatostatin analogues are highly effective in the management of the symptoms of carcinoid syndrome.

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Prospectus for the Future Further elucidation of the clinical and molecular epidemiologic mechanisms of gastrointestinal neoplasms will improve risk stratification and enable clinicians to tailor their use of screening and surveillance strategies, chemopreventive agents, and therapeutic options. Progress in our understanding of the cellular and molecular pathways that underlie neoplastic transformation and tumor

References Dicken BJ, Bigam DL, Cass C, et al: Gastric adenocarcinoma: Review and considerations for future directions. Ann Surg 241:27-39, 2005. Houghton J, Wang TC: Helicobacter pylori infection and gastric cancer: A new paradigm for inflammation-associated epithelial cancers. Gastroenterology 1281567-1281578, 2005. Levin B, Lieberman DA, McFarland B, et al: Screening and surveillance for the early detection of colorectal cancer and adenomatous Polyps, 2008: A joint guideline

progression will provide additional targets for selective pharmacologic or immunologic therapies. Technologic advances will facilitate the endoscopic diagnosis and treatment of premalignant and malignant diseases of the gastrointestinal tract.

from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 58:130-160, 2008. Shaheen N: Advances in Barrett esophagus and esophageal adenocarcinoma. Gastroenterology 128:1554-1566, 2005. Winawer SJ, Zauber AG, Fletcher RH, et al: Guidelines for colonoscopy surveillance after polypectomy: A consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology 130:1872, 2006.

Chapter

40

VII

Diseases of the Pancreas David R. Lichtenstein

Anatomy and Physiology The pancreas is an organ located in the retroperitoneum (Fig. 40-1) that weighs between 70 and 120 g and is about 12 to 20 cm in length. The head of the pancreas is nestled in the C loop of the duodenum, and the tail extends obliquely posterior to the stomach toward the hilum of the spleen. The pancreas consists of the pancreatic acinus and islet cells. The acinar cells compose more than 95%, and the islets about 1% to 2%, of the pancreatic mass. Hormones that the islets produce include insulin, glucagon, somatostatin, and pancreatic polypeptide. The functional exocrine unit of the pancreas is the pancreatic acinus, which is composed of both acinar and ductal epithelial cells. Acinar cells synthesize proteolytic digestive enzymes, which are packaged separately in the Golgi region into condensing vacuoles and transported in an inactive form referred to as zymogens to the apical portions of the cell, where they are discharged into the central ductule of the acinus by exocytosis. The ductules coalesce to form larger ducts, which empty into the duodenum at the ampulla of Vater. Inactive enzymes secreted into the duodenum are converted to an active form by enterokinase secreted from small bowel enterocytes. Trypsinogen, converted to active trypsin in the duodenum by enterokinase, is the trigger enzyme that subsequently converts the other zymogens to active enzymes (Fig. 40-2). Enzymes secreted in an active form include lipase, amylase, and ribonuclease. The ductal cells secrete primarily water and electrolytes, which decrease the viscosity of the protein-rich acinar secretions and alkalinize gastric contents emptied into the duodenum to levels at which the pancreatic enzymes become catalytically active (pH ranges from >3.5 to 4).

Normal Pancreas Development At about 4 weeks of gestation, the dorsal pancreas forms as an evagination from the duodenum, and shortly thereafter, the ventral pancreas forms from the hepatic diverticulum. Rotation of the duodenum places the two pancreatic buds in close proximity at 7 to 8 weeks of gestation, at which time

their main ducts begin to fuse. If fusion is incomplete, the duct of Wirsung drains only the ventral pancreas through the major ampulla, and the duct of Santorini drains the bulk of the pancreas (dorsal pancreas) through the relatively small accessory ampulla. This common anomaly, termed pancreas divisum, is present in 5% to 10% of the general population and may be associated with acute and chronic pancreatitis. Theories suggest that pancreatitis may result from relative outflow obstruction of the main dorsal duct through the small accessory ampulla. Endoscopic papillotomy or surgical sphincteroplasty are two therapeutic maneuvers that may reduce the incidence of recurrent pancreatitis by increasing drainage through the accessory papilla.

Acute Pancreatitis Acute pancreatitis is best defined as an acute inflammatory process of the pancreas that may also involve peripancreatic tissues and remote organ systems. The overall incidence is 1 in 4000 for the general population. Most patients with acute pancreatitis have a mild course and recover with restoration of normal pancreatic function and gland architecture. However, in 10% to 20%, the various pathways that contribute to increased intrapancreatic and extrapancreatic inflammation result in what is generally termed systemic inflammatory response syndrome (SIRS). In some instances, SIRS predisposes to multiple organ dysfunction or pancreatic necrosis. Early steps in the management of patients with acute pancreatitis can decrease severity, morbidity, and mortality. Prevention of the septic and nonseptic complications in patients with severe acute pancreatitis depends largely on monitoring, vigorous hydration, and early recognition of pancreatic necrosis and choledocholithiasis.

CAUSES AND PATHOGENESIS The pathogenesis of acute pancreatitis remains incompletely understood. Based on experimental models, the initiating event in acute pancreatitis is intra-acinar activation of trypsin from trypsinogen, resulting in acute intracellular injury, pancreatic autodigestion, and the potential for 445

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Minor ampulla

Dorsal duct (Santorini)

Pylorus

Table 40-1 Causes of Acute Pancreatitis

Tail of pancreas

Obstructive Causes Gallstones Tumors: ampullary or pancreatic tumors Parasites: Ascaris or Clonorchis species Developmental anomalies: pancreas divisum, choledochocele, annular pancreas Periampullary duodenal diverticula Hypertensive sphincter of Oddi Afferent duodenal loop obstruction Toxins Ethyl alcohol Methyl alcohol Scorpion venom: excessive cholinergic stimulation causes salivation, sweating, dyspnea, and cardiac arrhythmias; seen mostly in the West Indies Organophosphorus insecticides Drugs

Major ampulla

Common Ventral duct Head of bile duct (Wirsung) pancreas Figure 40-1 Normal anatomy of the pancreas.

Definite association (documented with rechallenges): azathioprine/6-mercaptopurine, valproic acid, estrogens, tetracycline, metronidazole, nitrofurantoin, pentamidine, furosemide, sulfonamides, methyldopa, cytarabine, cimetidine, ranitidine, sulindac, dideoxycytidine Probable association: thiazides, ethacrynic acid, phenformin, procainamide, chlorthalidone, l-asparaginase Metabolic Causes Hypertriglyceridemia, hypercalcemia, end-stage renal disease

ENTEROCYTES

GUT LUMEN Trypsinogen Enterokinase

Trypsin

Trypsinogen Chymotrypsinogen Proelastase Procarboxypeptidases A and B Prophospholipase A2 Trypsin Chymotrypsin Elastase Carboxypeptidases A and B Phospholipase A2

Figure 40-2 Mechanism of proenzyme activation in the intestinal lumen. (Adapted from Solomon TE: Exocrine pancreas: Pancreatitis. In The Undergraduate Teaching Project in Gastroenterology and Liver Disease, Unit 24. Bethesda, Md, American Gastroenterological Association, 1984.)

Trauma Accidental: blunt trauma to the abdomen (car accident, bicycle) Iatrogenic: postoperative, endoscopic retrograde cholangiopancreatography, endoscopic sphincterotomy, sphincter of Oddi manometry Infectious Parasitic: ascariasis, clonorchiasis Viral: mumps, rubella, hepatitis A, hepatitis B, non-A and non-B hepatitis, coxsackievirus B, echovirus, adenovirus, cytomegalovirus, varicella virus, Epstein-Barr virus, human immunodeficiency virus Bacterial: mycoplasma, Campylobacter jejuni, tuberculosis, Legionella species, leptospirosis Vascular Ischemia: hypoperfusion (such as postcardiac surgery) or atherosclerotic emboli Vasculitis: systemic lupus erythematosus, polyarteritis nodosa, malignant hypertension Idiopathic

profound systemic complications once activated enzymes are leaked into the bloodstream. Initiating events may include obstruction of the pancreatic duct (e.g., gallstones, pancreatic tumor), overdistention of the pancreatic duct (e.g., from endoscopic retrograde cholangiopancreatography [ERCP]), reflux of biliary or duodenal juices into the pancreatic duct, changes in permeability of the pancreatic duct, ischemia of the organ, and toxin-induced cholinergic hyperstimulation. During the initial hospitalization for acute pancreatitis, reasonable attempts to determine etiology is appropriate, particularly those causes that may affect acute management. The cause of acute pancreatitis is readily identified in 70% to 90% of patients after an initial evaluation consisting

Ten to 30% of patients with pancreatitis; up to 60% of these patients have occult gallstone disease (biliary microlithiasis or gallbladder sludge). Other less common causes include sphincter of Oddi dysfunction and mutations in the cystic fibrosis transmembrane regulator. Miscellaneous Penetrating peptic ulcer Crohn disease of the duodenum Pregnancy associated Pediatric association: Reye syndrome, cystic fibrosis

of history, physical examination, focused laboratory testing, and routine radiologic evaluation. Gallstones account for 45%, alcohol 35%, miscellaneous causes 10%, and idiopathic causes 10% to 20% of acute pancreatitis cases (Table 40-1).

Chapter 40—Diseases of the Pancreas

CLINICAL MANIFESTATIONS Abdominal pain is virtually always present and may be severe and refractory to analgesics. Pain often radiates to the back and is usually worse when supine. The onset may be swift with pain reaching maximal intensity within 30 minutes, is frequently unbearable, and characteristically persists for more than 24 hours without relief. Physical examination usually reveals severe upper abdominal tenderness at times associated with guarding. Ileus occurs when the inflammatory process extends into the small intestinal and colonic mesentery or when a chemical peritonitis occurs. Other manifestations include nausea, vomiting, and fever caused by the significant inflammatory process and release of cytokines (Fig. 40-3). In acute pancreatitis, a wide variety of toxic materials, including pancreatic enzymes, vasoactive materials (e.g., kinins), and other toxic substances (e.g., elastase, phospholipase A2), are liberated by the pancreas and extravasate along fascial planes in the retroperitoneal space, lesser sac, and the peritoneal cavity. These materials cause chemical

irritation and contribute to third-space losses of protein-rich fluid, hypovolemia, and hypotension. These toxic materials may also reach the systemic circulation by lymphatic and venous pathways and contribute to subcutaneous fat necrosis and end-organ damage, including shock, renal failure, and respiratory insufficiency (atelectasis, effusions, and acute respiratory distress syndrome [ARDS]). Grey Turner sign (ecchymosis of the flank) or Cullen sign (ecchymosis in the periumbilical region) may be seen in association with hemorrhagic pancreatitis. Metabolic problems are common in severe disease and include hypocalcemia, hyperglycemia, and acidosis. Hypocalcemia is most commonly caused by concomitant hypoalbuminemia. Other mechanisms may include complexing of calcium to released free fatty acids, protease-induced degradation of circulating parathyroid hormone (PTH), and failure of PTH to release calcium from bone. Local spread of inflammation leads to effects on contiguous organs that include gastritis and duodenitis, splenic vein thrombosis, colonic necrosis, and external compression of the common bile duct, leading to biliary obstruction. Trypsin can activate

Progression

Death 11. Intractable shock

10. Adult respiratory distress syndrome

9. Vasodilation, vascular permeability, shock, acute renal failure

Bile reflux Ethanol Trauma Other causes

1. Damage to ductal epithelium

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8. Activation of kallikrein system

7. Progression of injury (largely extrapancreatic in clinical manifestations)

4. Capillary and lymphatic injury 5. Capillary and lymphatic obstruction

6. Acinar cell injury and necrosis; release and activation of digestive enzymes and cell proteins

2. Leakage of 3. Activation of digestive juices proteolytic, lipolytic, or other enzymes in interstices of pancreas Figure 40-3 The pathophysiology of acute pancreatitis is not fully understood, but, as this schematic illustration implies, a cascade of events seems likely, beginning with the release of toxic substances into the parenchyma and ending with shock and death. Damage to the ductal epithelium or acinar cell injury may result from bile reflux, increased intraductal pressure, alcohol, or trauma. (Adapted from Grendell JH: The pancreas. In Smith LH Jr, Thier SO [eds]: Pathophysiology: The Biological Principles of Disease, 2nd ed. Philadelphia, WB Saunders, 1985, p 1228.)

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plasminogen to plasmin and induce clot lysis. On the other hand, trypsin can activate prothrombin and thrombin and produce thrombosis, leading to disseminated intravascular coagulation. Extrapancreatic fluid collections occur when fluid extravasates from the pancreas or surrounding leaky tissues. They are located in or near the pancreas and lack a wall of granulation or fibrous tissue. Acute fluid collections occur more commonly with severe pancreatitis. Most of these lesions regress spontaneously, and almost all remain sterile. The older term phlegmon was used in the past to describe inflammatory collections, but it is too ambiguous and imprecise for current use, given that it does not differentiate acute fluid collections from areas of pancreatic necrosis nor infected from noninfected collections. Pancreatic pseudocysts are defined as encapsulated nonepithelial lined collections of pancreatic juice, either pure or containing debris, single or multiple, small or large, and they can be located in or adjacent to the pancreas. Fluid collections must be present for a minimum of 4 weeks from the onset of pancreatitis to be termed a pseudocyst. Although most pseudocysts remain asymptomatic, presenting symptoms may include abdominal pain, early satiety, nausea, and vomiting due to compression of the stomach or gastric outlet. Rapidly enlarging pseudocysts may rupture, hemorrhage, obstruct the extrahepatic biliary tree, erode into surrounding structures, extend into the mediastinum, and become infected. Most pseudocysts less than 6 cm in diameter will resolve over time, and one third of lesions less than 10 cm in diameter remain asymptomatic or resolve. Indications for pseudocyst drainage include suspicion of infection or progressive enlargement with associated symptoms described previously. Asymptomatic pseudocysts should be followed. Pseudocysts can be drained surgically, percutaneously or endoscopically. The choice of treatment for symptomatic pseudocysts is frequently determined by the locally available expertise and by clinician preference because no method has been shown to be superior to the others. Pancreatic fistula occurs as a result of duct disruption and is treated with total parenteral nutrition, endoscopic stenting, and octreotide. Surgical intervention may be needed if the conservative approach is unsuccessful.

DIAGNOSIS The diagnosis of acute pancreatitis is based on a combination of clinical, biochemical, and radiologic factors. There is general acceptance that a diagnosis of acute pancreatitis requires two of the following three features: (1) abdominal pain characteristic of acute pancreatitis, (2) serum amylase or lipase more than 3 times the upper limit of normal, and (3) characteristic findings of acute pancreatitis on computed tomography (CT) scan. Elevated serum pancreatic enzymes may occur in a wide variety of other conditions, including bowel perforation, intestinal obstruction, mesenteric ische mia, tubo-ovarian disease, and renal failure. Serum lipase is slightly more specific and remains normal in some conditions associated with an elevation of serum amylase, including macroamylasemia, parotitis, and tubo-ovarian disease. The serum amylase level usually rises rapidly, as does the serum lipase level, and may remain elevated for 3 to 5 days. Serum lipase remains elevated longer than amylase and thus may be helpful if patients seek medical attention several days

after symptom onset. Repeated measurements of pancreatic enzymes have little value in assessing clinical progress, and the magnitude of serum amylase or lipase elevation does not correlate with the severity of pancreatitis. Macroamylase and macrolipase can occasionally cause isolated nonpathologic elevations of these enzymes, a situation in which the measurement of urinary clearance is useful. Pancreatic imaging with CT scanning can be used to confirm a diagnosis of pancreatitis (pancreatic enlargement, peripancreatic inflammatory changes, and extrapancreatic fluid collections). Selective CT scanning may also be useful in evaluating complications and assessing severity of disease (see later discussion), although a normal CT scan is present in 15% to 30% of mild cases. Acute gallstone pancreatitis should be suspected in patients with gallstones on ultrasonography or elevated liver tests, in particular an aspartate aminotransferase level elevated greater than threefold. Magnetic resonance imaging (MRI) is similar to CT with respect to imaging the inflamed pancreas and may be preferred in individuals at risk for contrast-induced injury (e.g., contrast allergy or renal insufficiency). However, recent studies also indicate the potential for gadolinium-induced nephrotoxicity with MRI examinations. MRI is also sensitive for the detection of necrosis, small neoplasms of the pancreas, and stones in the pancreaticobiliary tree.

SEVERITY OF DISEASE Supportive therapy alone is effective in treating 75% of all patients with acute pancreatitis. Twenty-five percent of patients, however, will suffer a complication, with one third succumbing to complications, yielding an overall mortality rate of 5% to 10%. Early deaths within the first 2 weeks are the result of multisystem organ failure caused by the release of inflammatory mediators and cytokines. Late deaths result from local or systemic infection. The risks for infection and death correlate with disease severity and the presence and extent of pancreatic necrosis. Therefore, a combination of clinical scoring and CT grade provides the most precise prognostic information. Patients should be stratified into mild or severe levels of illness based on well-established clinical criteria such as Ranson criteria (Table 40-2) or Acute Physiologic and Chronic Health Evaluation (APACHE II) scores. With increasing scores, the likelihood of a complicated, prolonged, and fatal outcome increases. The mortality rate is about 1% when fewer than three Ranson signs exist, 10% to 20% when three to five signs exist, and more than 50% when six Ranson signs exist. Similarly, an APACHE II score greater than 8 has been shown to predict severe pancreatitis. Conversely, a fatal outcome is unlikely with an APACHE II score less than 8. The distinction between interstitial and necrotizing acute pancreatitis has important prognostic implications (Fig. 40-4). Interstitial pancreatitis is characterized by an intact microcirculation and uniform enhancement of the gland on contrast-enhanced CT scanning. About 20% to 30% of patients with acute pancreatitis have necrotizing pancreatitis. Necrotizing pancreatitis is characterized by disruption of the pancreatic microcirculation so that large areas do not enhance on CT (Fig. 40-5). The presence of pancreatic necrosis predicts a worse severity of pancreatitis, particularly infection in the necrotic pancreatic tissue, also termed

Chapter 40—Diseases of the Pancreas Table 40-2 Signs Used to Assess Severity of Acute Pancreatitis At Time of Admission or Diagnosis Age > 55 yr White blood cell count > 16,000/mm3 Blood glucose > 200 mg/dL LDH > 2 × normal ALT > 6 × normal During Initial 48 Hours Decrease in hematocrit > 10% Serum calcium < 8 mg/dL Increase in blood urea nitrogen > 5 mg/dL Arterial Po2 < 60 mm Hg Base deficit > 4 mEq/L Estimated fluid sequestration > 600 mL ALT, alanine aminotransferase; LDH, lactate dehydrogenase; Po2, partial pressure of oxygen. Data from Ranson JH, Rifkind KM, Turner JW: Prognostic signs and nonoperative peritoneal lavage in acute pancreatitis. Surg Gynecol Obstet 43:209-219, 1976. By permission of Surgery, Gynecology and Obstetrics.

449

infected necrosis. Infected necrosis develops in 30% to 50% of patients with acute necrotizing pancreatitis but rarely in those with interstitial disease ( 7 g per 24 hours); however, the test is not specific for pancreatic exocrine insufficiency. The test also lacks sensitivity because steatorrhea will not occur in chronic pancreatitis until pancreatic lipase output falls to less than 5% to 10% of normal. The serum trypsinogen level correlates with functioning acinar parenchyma. A low level (2.5 to 3 mg/dL) results in jaundice and defines icteric hepatitis. Values higher than 20 mg/dL are uncommon and approximately correlate with the severity of disease. Elevations in serum alkaline phosphatase are usually limited to 3 times normal levels, except in cases of cholestatic hepatitis. A complete blood cell count most commonly shows mild leukopenia with atypical lymphocytes. Anemia and thrombocytopenia may also be present. The icteric phase of acute viral hepatitis may last days to weeks, followed by gradual resolution of symptoms and laboratory values.

SERODIAGNOSIS 1

2

3

4

6 5 Months

12

24

C Figure 43-2 Sequence of clinical and laboratory findings in (A) a patient with acute hepatitis A virus (HAV) infection, (B) a patient with hepatitis B virus (HBV) infection, and (C) a patient with hepatitis C virus (HCV) infection. ALT, alanine transaminase; HBc, hepatitis B core; HBe, hepatitis B early; HBeAg, hepatitis B early antigen; HBs, hepatitis B surface; HBsAg, hepatitis B surface antigen; IgG, immunoglobulin G; PCR, polymerase chain reaction.

risk, intravenous drug abusers, infants of infected mothers (vertical transmission), and health professionals. Patients with increased exposure to blood or blood products or with impaired immunity (e.g., patients undergoing dialysis and patients with leukemia, hemophilia, or trisomy 21 syndrome) are also highly susceptible to HBV. HCV was the main cause of post-transfusion hepatitis before 1992. It is presently the most common cause of hepatitis in intravenous drug users, and it accounts for a substan-

The ability to detect the presence of viral nucleic acids in hepatitis B, C, and D and antigen or antibodies to components of hepatitis A through E has fostered progress in the epidemiology of viral hepatitis. These viral markers are used in the diagnosis of acute viral hepatitis (see Fig. 43-2; Tables 43-2 and 43-3). An etiologic diagnosis is of great importance in planning preventive and public health measures pertinent to the close contacts of infected patients and in evaluating prognosis. Epstein-Barr virus and cytomegalovirus hepatitis may also be diagnosed by the appearance of specific antibodies of the immunoglobulin M (IgM) class. In acute hepatitis B, HBsAg and HBeAg are present in serum. Both are usually cleared within 3 months, but HBsAg may persist in some patients with uncomplicated cases for 6 months to 1 year. Clearance of HBsAg is followed after a variable “window” period by emergence of anti-HBs, which confers long-term immunity. Anti-HBc and anti-HBe appear in the acute phase of the illness, but neither provides immunity. Uncommonly, during the serologic window period, anti-HBc IgM, a marker of active viral replication suggesting recent infection, may be the only evidence of HBV infection. HDV infec-

Chapter 43—Acute and Chronic Hepatitis

469

Table 43-2 Serologic Markers of Viral Hepatitis Agent

Marker

Definition

Significance

Hepatitis A virus (HAV)

Anti-HAV IgM type IgG type

Antibody to HAV — —

Hepatitis B virus (HBV)

HBsAg

HBV surface antigen

HBeAg

HBe antigen; a component of the HBV core

— Current or recent infection or convalescence Current or previous infection; conferring immunity Positive in most cases of acute or chronic infection Transiently positive in acute hepatitis B

HBV DNA Anti-HBe

Anti-HBc (IgM or IgG)

Anti-HBs Hepatitis C virus (HCV)

Hepatitis D virus (HDV)

Antibody to HBV core antigen

Positive in late convalescence in most acute cases Anti-HCV

Antibody to HBV surface antigen and after vaccination Antibodies to a group of recombinant HCV peptides

HCV RNA

Infectious viral genomic material Antibody to HDV antigen Viral peptide Infectious viral genomic material

Anti-HDV (IgM or IgG) HDV antigen HDV RNA

Hepatitis E virus (HEV)

Infectious viral genomic material Antibody to HBe antigen

Anti-HEV (IgM or IgG)

Antibody to HEV antigen

May persist in chronic infection Reflection of presence of viral replication, whole Dane particles in serum, high infectivity Serum level reflects degree of viral replication; predicts response to therapy Transiently positive in convalescence Persistently present in some chronic cases Usually a reflection of low infectivity Positive in all acute and chronic cases Reliable marker of infection, past or current IgM anti-HBc a reflection of active viral replication and acute infection Not protective Confers immunity Positive on average 12 wk after exposure; not protective Persistent in acute, chronic, or past infection Reflects ongoing infection, level inversely linked to treatment response Acute or chronic infection seen with positive HBsAg; not protective IgM and IgG clear in resolving infection IgG persists in chronic infection Persists in chronic infection Most reliable test for acute or chronic infection Acute or chronic infection IgM may persist up to 6 months

IgG, immunoglobulin G; IgM, immunoglobulin M.

tion superimposed on HBV infection is most reliably detected by polymerase chain reaction (PCR) testing for HDV RNA. Other possible tests include HDV antigen and anti-HDV (IgM and IgG antibodies). Acute hepatitis C can be detected using a sensitive PCR assay for HCV RNA within 2 weeks of exposure. Serum antibodies to HCV develop within 12 weeks of exposure or within 4 to 5 weeks after biochemical abnormalities are discovered. At onset of symptoms, 30% of patients will be missed if checked by serum enzyme immunoassay (EIA) for HCV antibody alone. Commercial EIAs for hepatitis E to detect both IgM and IgG class antibodies are also available but may lack general sensitivity and specificity. The HEV IgM antibody is present for up to 6 months after exposure.

COMPLICATIONS Cholestatic Hepatitis In some patients, most commonly during HAV infection, a self-limited period of cholestatic jaundice may supervene that is characterized by marked conjugated hyperbilirubinemia, elevation of alkaline phosphatase, and pruritus. Investigation may be required to differentiate this condition from mechanical obstruction of the biliary tree (see Chapter 45).

Fulminant Hepatitis Massive hepatic necrosis occurs in less than 1% of patients with acute viral hepatitis and leads to a devastating and often

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Section VIII—Diseases of the Liver and Biliary System

Table 43-3 Interpretation of Serologic Markers and Serum DNA in Hepatitis B HBsAg HBeAg Acute hepatitis Acute hepatitis, window period Recovery from acute hepatitis Chronic hepatitis Chronic hepatitis (precore mutant) Inactive carrier Vaccinated

+

+/−

+ +

+

Anti-HBc IgM Anti HBc IgG Anti-HBs Anti-HBe HBV DNA* + + +

+

+

+

+/− +

+

+ +

+/− +

HBsAg, hepatitis B surface antigen; HBeAg, hepatitis Be antigen; anti-HBc IgM, hepatitis B core antibody (IgM type); anti-HBc IgG, hepatitis B core antibody (IgG type); anti-HBs, hepatitis B surface antibody; anti-HBe, hepatitis Be antibody; HBV DNA, hepatitis B viral DNA. *HBV DNA > 105 copies/mL.

fatal condition called fulminant hepatic failure. This condition is discussed in detail in Chapter 44.

Chronic Hepatitis Hepatitis A does not progress to chronic liver disease, although occasionally it has a relapsing course. Persistence of aminotransferase elevation and viral antigens or nucleic acids beyond 6 months in patients with hepatitis B and C suggests evolution to chronic hepatitis, although slowly resolving acute hepatitis may occasionally lead to such test abnormalities for up to 12 months, with eventual complete resolution. Chronic hepatitis is considered in detail later in this chapter.

Rare Complications Acute viral hepatitis may be followed by aplastic anemia, which affects mostly male patients and results in a mortality rate of greater than 80%. Pancreatitis, myocarditis, pericarditis, pleural effusion, and neurologic complications, including Guillain-Barré syndrome, aseptic meningitis, and encephalitis, have also been reported. Cryoglobulinemia and glomerulonephritis are associated with hepatitis B and C, and polyarteritis nodosa with hepatitis B.

MANAGEMENT All cases of acute hepatitis A, B, and E, unless complicated by fulminant hepatitis, are self-limited (see Table 43-2). Treatment of acute hepatitis C is important, and recent data support that early treatment within 12 weeks of diagnosis with pegylated interferon-α induces high sustained virologic response rates. Studies of antiviral therapy in acute hepatitis B have not shown clear benefit, although many experts advocate use of nucleoside or nucleotide analogues, specifically in the setting of acute liver failure due to hepatitis B. The treatment in all other cases is largely supportive and includes rest, maintenance of hydration, and adequate dietary intake. Most patients show a preference for a low-fat, high-carbohydrate diet. Alcohol should be avoided. Vitamin supplementation is of no proven value, although vitamin K may be indicated if prolonged cholestasis occurs. Nausea can be treated with small doses of metoclopramide and hydroxyzine. Hospitalization is indicated for patients with severe nausea and vomiting and for those with evidence of deteriorating liver function, such as hepatic encephalopathy or pro-

longation of the prothrombin time. In general, hepatitis A and E may be regarded as noninfectious after 3 weeks, whereas hepatitis B is potentially infectious to sexual contacts throughout its course, although the risk is low once HBsAg has cleared.

PREVENTION Both feces and blood from patients with hepatitis A and E contain virus during the prodromal and early icteric phases of the disease (see Fig. 43-2). Raw shellfish concentrate the HAV from sewage pollution and may serve as vector of the disease. General hygienic measures should include hand washing by contacts and careful handling, disposal, and sterilization of excreta and contaminated clothing and utensils. Close contacts of patients with hepatitis A should receive anti-HAV serum immunoglobulin as soon as possible after exposure. HAV vaccination is appropriate for children and travelers to endemic areas, individuals with immunodeficiency or chronic liver disease, and those with high-risk behaviors or occupations. Recently, a recombinant vaccine for HEV has been shown to be safe and effective in a highrisk population (healthy adults in an endemic area) in a randomized controlled trial, but formal guidelines for its use have not been established. Hepatitis B is rarely transmitted by body fluids other than blood. However, it is highly infectious, and strict adherence to universal precautions is mandatory. Efforts at preventing hepatitis B have involved the use of immunoglobulin-enriched anti-HBs (HBIG) and recombinant HBV vaccines. Postexposure prophylaxis with HBIG after blood or mucosal exposure (e.g., needlestick, eye splash, sexual contacts of patients with acute hepatitis B, neonates born to mothers with acute or chronic infection) should be given within 7 days along with HBV vaccine. Preventive vaccination is currently recommended for highrisk groups and individuals (health care professionals, patients undergoing dialysis, patients with advanced liver disease or hemophilia, residents and staff of custodial care institutions, sexually active homosexual men) and is advocated universally for children. No accepted prevention strategies are available for HCV. Serum immunoglobulin is not useful for postexposure prophylaxis. The advent of widespread blood product screening for anti-HCV has made post-transfusion hepatitis a rarity.

Chapter 43—Acute and Chronic Hepatitis

Alcoholic Fatty Liver and Hepatitis Alcohol abuse is a major cause of liver disease in the Western world. Three major pathologic lesions resulting from alcohol abuse are (1) fatty liver, (2) alcoholic hepatitis, and (3) cirrhosis. These lesions are not mutually exclusive, and there may be features of all three lesions in the same patient. The first two lesions are potentially reversible and may sometimes be confused clinically with viral hepatitis or gallbladder or biliary tract disease. Alcoholic cirrhosis is discussed in Chapter 45.

MECHANISM OF INJURY Mechanisms of liver injury caused by alcohol are complex. Ethanol and its metabolites, acetaldehyde and nicotinamide adenine dinucleotide phosphate (NADP), are directly hepatotoxic and cause a large number of metabolic derangements. Induction of cytochrome P-450 (CYP2E1) and cytokine pathways, particularly tumor necrosis factor-α (TNF-α), is also critical in initiating and perpetuating hepatic injury and producing the lesions of alcoholic hepatitis. Hepatotoxic effects from alcohol vary considerably among individuals. Nevertheless, consumption by men of 40 to 80 g of ethanol per day (one beer or one mixed drink = 10 g of ethanol) for 10 to 15 years carries a substantial risk for the development of alcoholic liver disease, whereas women appear to have a lower threshold of injury. Malnutrition and presence of other forms of chronic liver disease may potentiate the toxic effects of alcohol on the liver, and genetic factors may contribute to individual susceptibility.

CLINICAL AND PATHOLOGIC FEATURES Alcoholic fatty liver may exhibit as incidentally discovered tender hepatomegaly. Some patients consult a physician because of pain in their right upper quadrant. Jaundice is rare. Aminotransferases are mildly elevated (10 to 15 g), the formation of excess toxic metabolites depletes the available glutathione and produces necrosis. Acetaminophen overdose, commonly taken in a suicide attempt, leads to nausea and vomiting within a few hours. These symptoms subside and are followed in 24 to 48 hours by clinical and laboratory evidence of hepatocellular necrosis (raised aminotransferase levels) and hepatic dysfunction (prolonged prothrombin time and hepatic encephalopathy). Similar findings may occur with therapeutic doses of acetaminophen in patients with chronic alcoholism or malnutrition. Extensive liver necrosis may lead to fulminant hepatic failure and death. In a patient with nonstaggered overdose, a serum acetaminophen level should be drawn 4 to 24 hours after ingestion. If plotted on a treatment nomogram of plasma drug concentration against time, it can predict the severity of outcome and need for therapy. Treatment with N-acetylcysteine given orally (140-mg/kg bolus followed by 70 mg/kg × 17 doses) or intravenously, thought to promote hepatic glutathione synthesis, may be life saving. Nonsteroidal anti-inflammatory drugs (NSAIDs) as a class are an important cause of drug-induced liver disease. Salicylates cause dose-dependent hepatocellular injury that is usually clinically mild and easily reversible. Diclofenac, one of the most commonly prescribed NSAIDs worldwide, has been linked to asymptomatic elevation of aminotransferases, acute hepatitis, and fulminant hepatic failure. Sulindac is considered the most likely NSAID to produce hepatic injury and causes a damage spectrum ranging from hepatocellular to mixed to pure cholestatic injury. Whether the newer cyclo-oxygenase-2–selective NSAIDs have a lower risk for hepatotoxicity is uncertain.

ANTIBIOTICS AND ANTIVIRALS Antimicrobials as a class are the most frequently incriminated agents causing drug-induced liver injury. Amoxicillin–clavulanic acid is the leading cause of antibiotic-related liver injury and results in a cholestatic hepatitis. Men appear to be more susceptible than women. Other common agents include nitrofurantoin, isoniazid, trimethoprim-sulfamethoxazole, and fluoroquinolones. Isoniazid, as a singledrug prophylaxis against tuberculosis, commonly produces raised serum aminotransferase levels in 20% of patients. This effect appears to be transient and self-limited in most patients. However, a 1% incidence exists of clinical hepatitis,

Chapter 43—Acute and Chronic Hepatitis which progresses to fatal hepatic necrosis in 10% of affected patients. Individual and age-related differences in hepatic acetylation of potentially toxic isoniazid metabolites may be important in this injury. Thus, the incidence of severe hepatic damage increases with age such that significant elevation of aminotransferase levels in persons who are older than 35 years is an indication for discontinuing the drug. Erythromycin is an established agent causing cholestatic injury. Trimethoprim-sulfamethoxazole characteristically causes cholestatic or mixed injury. A large number of agents used to treat HIV infection have been linked with hepatic injury of various forms. Important among these agents are nevirapine, ritonavir, and indinavir.

CENTRAL NERVOUS SYSTEM AGENTS Central nervous system agents are second only to antimicrobials as a frequent cause of drug-induced liver injury. Important categories are anticonvulsants and anesthetics. Other common agents include duloxetine, bupropion, and fluoxetine. Among anticonvulsants, sodium valproate, phenytoin, carbamazepine, and lamotrigine are the most common drugs causing liver injury. Phenytoin and carbamazepine have been implicated in an antiepileptic hypersensitivity syndrome, characterized by a triad of rash, fever, and hepatocellular injury that may lead to fulminant hepatic failure. Lymphadenopathy and a mononucleosis-like picture with atypical lymphocytes may be present. Renal and pulmonary involvement may also occur. Historically, the anesthetic agent halothane caused an uncommon acute viral hepatitis– like reaction several days after exposure in susceptible persons. Hepatic injury was caused in part by an allergic response to hepatic neoantigens produced by halothane metabolism, and the severity of this reaction increased with repeated exposure. Newer, commonly used halogenated anesthetic agents (e.g., isoflurane, enflurane) are hepatotoxic in a much smaller number of patients, though cross-sensitivity does exist.

HERBS Herbal supplements are taken throughout the world, and about $5 billion per year is spent in the United States alone on herbal agents. Incorrectly considered to be safe because they are natural, many herbs are hepatotoxic. Senecio, Heliotropium, Crotalaria, and comfrey contain pyrrolizidine alkaloids that cause hepatic veno-occlusive disease. Hepatotoxicity ranging from mild hepatitis to massive necrosis and fulminant hepatic failure has been associated with the use of chaparral, germander, pennyroyal oil, mistletoe, valerian root, comfrey, and Ma huang. Milk thistle, often taken by patients with chronic hepatitis and cirrhosis, has not been associated with hepatotoxicity, but its benefit is undefined because of a lack of controlled studies.

Chronic Hepatitis Chronic hepatitis is defined as a hepatic inflammatory process that fails to resolve after 6 months and, in those with acute viral hepatitis, by persistence of serum viral antigens and nucleic acids beyond a similar period.

473

ETIOLOGY Acute viral hepatitis can ultimately lead to chronic hepatitis, with the notable exceptions of HAV and HEV. Nonalcoholic steatohepatitis (NASH) is now considered the most frequent cause of chronic hepatitis in the United States and Western Europe. Several drugs may produce chronic hepatitis, the best recognized being methyldopa. In contrast to acute hepatitis, an etiologic agent is sometimes difficult to identify in cases of chronic hepatitis. The pathogenesis of these idiopathic forms may represent quiescent autoimmune disease, undetected past drug-induced injury or NASH, antibodynegative viral infections, or misdiagnosed cholestatic liver injury (e.g., primary biliary cirrhosis, primary sclerosing cholangitis).

CLASSIFICATION Current classification of chronic hepatitis is based on the etiologic agent responsible for disease, the grade of injury (determined by the numbers and location of inflammatory cells), and the stage of disease on liver biopsy (determined by the degree, location, and distortion of normal architecture by fibrosis). This classification allows integration of knowledge of the natural history of specific causes with histologic features of hepatic damage to assess the severity and prognosis of the process. Thus, in general, biochemical and serologic studies along with liver biopsy are used in the diagnosis and management of chronic hepatitis.

Chronic Viral Hepatitis Chronic hepatitis B follows acute hepatitis B in 5% to 10% of adults in the United States. HBV infection without evidence of any liver damage may persist, resulting in asymptomatic or healthy hepatitis B carriers. In Asia and Africa, many such carriers appear to have acquired the virus from infected mothers during infancy (vertical transmission). Patients who are HBsAg and HBeAg positive and have high serum HBV DNA (>20,000 IU/mL or >100,000 copies/mL), coupled with increased serum aminotransferases (ALT, 2 times normal) are in a high replicative phase (see Table 43-3). In contrast, patients in a low replicative phase are HBsAg and anti-HBe positive, have low serum HBV DNA (10 mm Hg). The HVPG is measured using a transvenous approach by subtracting free hepatic venous pressure from the wedged hepatic venous pressure. Although cirrhosis is the most important cause of portal hypertension, any process leading to increased resistance to portal blood flow into (presinusoidal) or through (sinusoidal) the liver or to hepatic venous outflow from the liver (postsinusoidal) may result in portal hypertension (Table 45-3). In addition, cirrhosis is associated with increased cardiac output, which leads to greater splanchnic blood flow, further aggravating portal hypertension. It is important to recognize that the HVPG is reliably increased only in sinusoidal portal hypertension. In an attempt to decompress the portal system, venous collaterals form between the portal and systemic circulations. Major sites of collateral vessel formation include the gastroesophageal junction, retroperitoneum, rectum, and falciform ligament of the liver (abdominal and periumbilical collaterals). Clinically, the most important collaterals are those connecting the portal vein to the azygos vein through dilated, tortuous veins (varices) in the submucosa of the gastric fundus and esophagus.

Table 45-3 Causes of Portal Hypertension Increased Resistance to Flow Presinusoidal Extrahepatic • Portal or splenic vein occlusion (thrombosis, sclerosis, tumor) Intrahepatic • Schistosomiasis • Congenital hepatic fibrosis • Sarcoidosis Sinusoidal Cirrhosis (many causes) Alcoholic hepatitis Postsinusoidal Intrahepatic • Veno-occlusive disease Extrahepatic • Budd-Chiari syndrome • Cardiac causes: constrictive pericarditis Increased Portal Blood Flow Splenomegaly not caused by liver disease Arterioportal fistula

Variceal Hemorrhage Gastroesophageal varices may develop when the portal pressure gradient exceeds 10 mm Hg, and the risk for variceal rupture leading to hemorrhage occurs when the gradient is greater than 12 mm Hg. Hemorrhage develops in 10% to 30% of patients every year, and each episode of variceal hemorrhage is associated with a mortality rate as high as

Chapter 45—Cirrhosis of the Liver and Its Complications Primary Prevention (nonselective β blockers and/or mononitrates)

Treating first variceal hemorrhage

1. Somatostatin or analogues 2. Endoscopic therapy 3. Antibiotic prophylaxis

Successful

Unsuccessful

Secondary prevention 1. Endoscopic ablation therapy and 2. Nonselective β blockers

1. Sengstaken-Blakemore tube 2. Portal systemic shunt surgery Portacaval anastomosis TIPS Distal splenorenal shunt

Consider for liver transplantation Figure 45-2 Prevention and treatment of variceal bleeding. TIPS, transjugular intrahepatic portosystemic shunt.

15% to 30%. Bleeding occurs most commonly from large varices in the esophagus when high tension in the walls of these vessels leads to rupture. Among gastric varices, fundal varices have the highest rate of bleeding and may bleed with portal pressure gradients of less than 12 mm Hg. Variceal bleeding usually causes painless hematemesis, melena, or hematochezia, which typically leads to hemodynamic compromise (see Chapter 34), further aggravated by impaired hepatic synthesis of coagulation factors (from hepatocellular dysfunction) and thrombocytopenia (from hypersplenism). The management of gastroesophageal varices includes the treatment of acute variceal hemorrhage, the prevention of rebleeding (secondary prophylaxis), and the prevention of the initial episode of bleeding (primary prophylaxis) (Fig. 45-2). In the setting of acute variceal hemorrhage, the initial intervention consists of hemodynamic resuscitation with colloids such as blood or fresh-frozen plasma and airway protection and ventilatory support, if necessary. Combined pharmacologic and endoscopic therapy is superior to either therapy alone, especially if pharmacologic therapy is instituted immediately. In addition, prophylactic intravenous antibiotics should be administered early because they reduce the risk for infection, rebleeding, and death. Current pharmacologic therapy consists of somatostatin or its synthetic analogues (i.e., octreotide, vapreotide). These agents are best instituted before endoscopic examination. Endoscopic therapy includes band ligation and/or sclerotherapy (Web Video 45-1). Prospective studies have demonstrated that band ligation is the preferred modality given the lower inci-

481

dence of adverse effects and complications. In patients with gastric variceal hemorrhage, endoscopic variceal ablation with cyanoacrylate glue is superior to band ligation, although this therapy is not approved in the United States. Balloon tamponade (Sengstaken-Blakemore tube, Linton tube, or Minnesota tube) is a temporary measure reserved for patients in whom endoscopic therapy fails in the setting of massive hemorrhage. These patients may need to undergo portal decompression through a surgical shunt or transjugular intrahepatic portosystemic shunt (TIPS) placement. After an initial episode of variceal bleeding, recommendations for secondary prophylaxis include a combination of nonselective β blockers (propranolol and nadolol) and variceal obliteration through repeated courses of endoscopic band ligation. However, individual patient characteristics may dictate whether nonselective β blockers can be used. There are no formal recommendations on frequency and duration of follow-up endoscopy, although it is generally done at 1- to 6-month intervals after obliteration of varices. Endoscopic screening has been recommended to identify patients at high risk for variceal bleeding (i.e., those with large varices) so that primary prophylaxis can be instituted. Several studies suggest that certain clinical features (e.g., thrombocytopenia, ascites, telangiectasias) may help predict patients who are likely to have large varices, but given the poor predictive values of these features, endoscopic screening should be performed in all patients newly diagnosed with cirrhosis. Capsule endoscopy has been evaluated as a less invasive screening alternative to upper endoscopy but is currently less sensitive in diagnosing varices. Primary prophylaxis should be instituted for all patients with large varices and in those with advanced liver disease (Child class B and C) with small varices. Nonselective β blockers are the agents of choice for primary prophylaxis because they reduce portal blood flow and vascular resistance and hence portal pressure. In patients with contraindications or intolerance to β blockers, variceal obliteration through endoscopic band ligation is the best alternative.

Ascites Ascites is the accumulation of excess fluid in the peritoneal cavity. Although cirrhosis is the most common cause of ascites, this condition may have numerous other causes (Table 45-4). The serum ascites-albumin gradient has replaced the exudative-transudative classification of ascites. An elevated serum ascites-albumin gradient (>1.1 g/dL, serum albumin concentration–ascites albumin concentration) signifies the presence of portal hypertension. Ascites becomes clinically detectable with fluid accumulation greater than 500 mL. Shifting dullness to percussion is the most sensitive clinical sign of ascites, but ultrasonography can readily detect smaller fluid volumes (250 mL). The precise sequence of events leading to the development of cirrhotic ascites remains debated. However, both excess renal sodium and water retention resulting from portal hypertension and splanchnic vasodilation resulting in overflow of fluid into the peritoneum (overflow theory) and decreased effective circulating blood volume resulting from systemic arterial vasodilation leading to activation of

482

Section VIII—Diseases of the Liver and Biliary System

neurohumoral systems and sodium and water retention (underflow theory) play a role. Management of cirrhotic ascites consists initially of sodium restriction, preferably to less than 2 g per day. Restricted fluid intake may be necessary if hyponatremia (1.1 g/dL

Low: λ) γ, α, or µ heavy chain or fragment Free light chain (λ > κ) IgG > IgM > IgA, usually without urinary light-chain secretion M protein occasionally secreted; IgM > IgG M protein occasionally secreted; IgM > IgG

Nonlymphoid Neoplasms Chronic myelogenous leukemia Carcinomas (e.g., colon, breast, prostate)

No consistent patterns No consistent patterns

Autoimmune or Autoreactive Disorders Cold agglutinin disease Mixed cryoglobulinemia Sjögren syndrome

IgM κ most common IgM or IgA IgM

Anti-I antigen Anti-IgG

Miscellaneous Inflammatory, Storage, or Infectious Disorders Lichen myxedematosus Gaucher disease Cirrhosis, sarcoid, parasitic diseases, renal acidosis

IgG λ IgG No consistent pattern

IgA, immunoglobulin A; IgD, immunoglobulin D; IgG, immunoglobulin G; IgM, immunoglobulin M. Modified from Salmon SE: Plasma cell disorders. In Wyngaarden JB, Smith LH Jr (eds): Cecil Textbook of Medicine, 18th ed. Philadelphia, WB Saunders, 1988, p 1026.

Chapter 51—Disorders of Lymphocytes occurs in about 1% of patients per year. Distinguishing patients with stable, nonprogressive MGUS from patients in whom multiple myeloma will eventually develop is difficult. The risk for progression is greater in patients with IgA or IgM M proteins and in patients with initial concentrations of M protein in excess of 1.5 g/dL. Although no definitive evidence has been found that monitoring patients with the diagnosis of MGUS improves survival, patients should undergo annual evaluation, including serum electrophoresis, to detect progression to multiple myeloma before the onset of overt symptoms or complications.

MULTIPLE MYELOMA Multiple myeloma is a malignant plasma cell disorder characterized by neoplastic infiltration of the bone marrow and bone and the presence of monoclonal immunoglobulin or light chains in the serum or urine. The diagnosis of multiple myeloma is made by identifying an increase in the number of plasma cells in the bone marrow (>30%) and a serum M protein other than IgM exceeding 3 g/dL for IgG or 2 g/ dL for IgA or a urine M protein exceeding 1 g per 24 hours. Patients with lower levels of M protein or less than 30% bone marrow plasmacytosis may still be diagnosed with myeloma based on the presence of a combination of other features such as hypogammaglobulinemia, lytic bone lesions, or plasmacytoma. For patients lacking these features, the major differential diagnosis is usually between MGUS and myeloma; in some cases, the distinction can only be made by serial follow-up of the patient with evidence of rising M protein levels or the development of associated clinical manifestations of myeloma. About 20% of patients with multiple myeloma do not have detectable serum M protein by standard electrophoresis but have circulating free light chains that appear in the urine (Bence Jones protein) that can be detected in a 24-hour urine collection by urine protein electrophoresis (light-chain disease). In rare cases, patients with nonsecretory myeloma have neither detectable serum nor urine M protein. However, in these patients, a monoclonal population of plasma cells can be detected by immunohistochemical identification of cytoplasmic lightchain–restricted immunoglobulin. Quantitative assays for detection of free light chains in the serum of patients with multiple myeloma have now become widely available and may be used to assess disease in a similar fashion to electrophoretic measurements. These assays are quite sensitive and may provide measurement of clonal protein in patients thought to have nonsecretory disease by other methods. Free light chains have a relatively short half-life in the circulation, 2 to 6 hours, in comparison with weeks for intact immunoglobulin molecules and may therefore be used to obtain a more rapid assessment of disease response for patients on therapy. The clinical manifestations of multiple myeloma relate to the direct effects of bone marrow and bone infiltration by malignant plasma cells, the systemic effects of the M protein, or the effects of the concomitant deficiency in humoral immunity that occurs in this disease. The most common symptom in multiple myeloma is bone pain. Bone radiographs typically show pure osteolytic punched-out lesions, often in association with generalized osteopenia and pathologic fractures. Bony lesions can show as expansile masses

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associated with spinal cord compression. Hypercalcemia caused by extensive bony involvement is common in myeloma and may dominate the clinical picture. Anemia occurs in most patients as a result of marrow infiltration and suppression of hematopoiesis and results in fatigue; granulocytopenia and thrombocytopenia are less common. Patients with myeloma are susceptible to bacterial infections because of impaired production and increased catabolism of normal immunoglobulins. Respiratory tract infections from Streptococcus pneumoniae, Staphylococcus aureus, H. influenzae, and Klebsiella pneumoniae, and gram-negative urinary tract infections are common. Renal insufficiency occurs in about 25% of patients with myeloma. The cause of renal failure in these patients is often multifactorial; hypercalcemia, hyperuricemia, infection, and amyloid deposition can contribute. However, direct tubular damage from light-chain excretion is invariably present. M proteins can also cause a host of diverse effects because of their physicochemical properties. These effects include cryoglobulinemia, hyperviscosity, amyloidosis, and clotting abnormalities resulting from interaction of the M protein with platelets or clotting factors. Several staging or classification systems exist for myeloma. The three-tier staging system for myeloma is a functional system that correlates with survival (Table 51-7). In contrast to the anatomic staging systems used for lymphomas and solid tumors, myeloma staging is based on clinical tests (bone radiographs) and laboratory tests (hemoglobin, serum calcium, serum or urine M protein levels, and serum creatinine) that correlate with tumor burden. Adverse prognostic factors include advanced stage, impaired renal function, elevated LDH levels, abnormal bone marrow cytogenetics, depressed serum albumin levels, and elevated β2-microglobulin levels. The last is the single most powerful predictor of survival. Recently, a simplified prognostic scheme, the International Staging System for Myeloma, identified three stages with distinct prognosis based on only two variables: β2-microglobulin and albumin levels. A classification system proposed by the International Myeloma

Table 51-7 Myeloma Staging System Stage

Criteria

I

All of the following: 1. Hemoglobin >10 g/dL 2. Serum calcium 6 mo Lifelong

*Long-term therapy must be adjusted individually according to other diseases, risks for bleeding, presence of transient risk factors, and ease of compliance. † Inherited risk factors include factor V Leiden; prothrombin 20210A; deficiencies of antithrombin III, protein C, or protein S. VTE/PE, venous thromboembolism/pulmonary embolism.

Table 54-8 Drugs that Affect Warfarin Levels Drugs that Increase Warfarin Levels: Prolonged INR ↓ Warfarin clearance Disulfiram Metronidazole Trimethoprim-sulfamethoxazole ↓ Warfarin-protein binding Phenylbutazone ↑ Vitamin K turnover Clofibrate Drugs that Decrease Warfarin Levels: Subtherapeutic INR ↑ Hepatic metabolism of warfarin Barbiturates Rifampin ↓ Warfarin absorption Cholestyramine ↑, Increased; ↓, decreased; INR, international normalized ratio.

warfarin is a teratogen; effective contraception should be used concurrently in women of childbearing age. Supratherapeutic INR levels commonly occur with warfarin therapy, with or without bleeding. In patients with moderately elevated INR values (>5) with little or no bleeding, temporary discontinuation of warfarin and reinstitution of the drug at a lower maintenance dose may be sufficient. Patients with higher INR values (5 to 9) without serious bleeding should have warfarin withheld and receive low doses (1 to 2.5 mg per day) of oral vitamin K to reach therapeutic INR levels; parenteral vitamin K can be given if gastrointestinal function is problematic. When serious active bleeding occurs with high INR values, especially if surgery is required to correct the bleeding, a combination of vitamin K and transfusion of plasma (see Chapter 53) will rapidly correct the INR. The INR can become elevated as a result of concurrent use of drugs that increase free warfarin levels (Table 54-8). Whenever bleeding occurs as a complication of anticoagulation, serious consideration must be given to

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Section IX—Hematologic Disease

future bleeding risks and to whether the patient requires prophylactic IVC filter placement.

Antithrombotic Therapy during Pregnancy Heparins, both UFH and LMWH, are the safest therapy for venous thrombosis during pregnancy; heparin does not cross the placenta, unlike warfarin, which causes a characteristic fetal embryopathy. Warfarin also causes fetal hemorrhage and placental abruption and should be avoided during pregnancy. VTE or PE during pregnancy should be treated with intravenous UFH for 5 to 10 days, followed by an adjusted-dose regimen of subcutaneous UFH, starting with 20,000 U every 12 hours and adjusted to achieve a PTT higher than 1.5 times baseline at 6 hours after injection. An attractive alternative to UFH during pregnancy is LMWH, which can be given subcutaneously once or twice daily and does not require monitoring. Suprarenal IVC filters have also been used successfully during pregnancy without significant morbidity. In women with aPL syndrome who become pregnant, therapy is critical to prevent fetal loss; aspirin (160 mg) is combined with prophylactic doses of either subcutaneous UFH (10,000 to 15,000 U per day in divided doses) or LMWH (to achieve an anti-Xa level of 0.1 to 0.3 U/mL). When such women have a history of TE disease, therapeutic doses of LMWH or UFH plus aspirin are employed. Heparin should be discontinued at the time of labor and delivery, although the risk for hemorrhage is not high during delivery, especially if anti-Xa levels are less than 0.7 U/mL. One concern with residual anticoagulation at delivery is the risk for spinal hematoma with epidural anesthesia; this concern has been reported with both UFH and LMWH. The anti-Xa level that is safe for an epidural procedure is not known. Protamine sulfate can be used to neutralize UFH if the PTT is prolonged during labor and delivery; however, LMWH is only partially (10%) reversed by protamine.

Anticoagulation during the postpartum period can be carried out with heparin or warfarin; neither drug is contraindicated during breastfeeding. Women receiving long-term warfarin therapy (e.g., for valvular heart disease) who wish to become pregnant need to be switched to a fully anticoagulating dose of UFH or LMWH; warfarin treatment can be restarted postpartum.

Perioperative Anticoagulation A common clinical problem is the management of anticoagulation in patients who require surgery. The principles of care in this situation reflect the need for adequate hemostasis during and immediately after surgical procedures and the critical importance of restarting anticoagulation as soon as possible postoperatively, especially because surgery itself represents a relative hypercoagulable state. In patients with VTE who are anticoagulated on a short-term basis (3 cm, ≤7 cm, and located more than 2 cm from the carina. No lymph nodes are involved. Tumor size is ≤7 cm and located more than 2 cm from carina. Peribronchial and/or hilar nodes may be involved. Tumor size is ≤7 cm located more than 2 cm from carina with peribronchial and/or hilar nodes involved; or tumor size >7 cm (or satellite tumors within the same lobe) with invasion of chest wall, diaphragm, mediastinal pleura, pericardium, or located less than 2 cm from the carina, without lymph node involvement. Any size tumor is present and may have invaded chest wall, carina, heart, great vessels, trachea, and esophagus. Tumor may involve ipsilateral peribronchial, hilar, mediastinal, and/or subcarinal nodes. Any size tumor is present and may have invaded any structure. Nodal involvement is always present and may extend to contralateral mediastinum or supraclavicular or scalene area. Metastases are present (including a malignant pleural effusion).

Small Cell Lung Cancer Limited

Extensive

Tumor is confined to one lung. Nodes may involve contralateral lung, but all cancer must be encompassed in one radiation portal. Metastatic disease is present or disease is not limited to one radiation field.

Non–Small Cell Lung Cancer The goals of staging for NSCLC are to find patients who may be cured by resection. Therefore, attention to the mediastinum, a common site of lymph node spread, and a search for metastatic disease are both performed as soon as possible after diagnosis. Testing usually begins with a CT scan extending through the liver and adrenal glands, common sites of metastases. Bronchoscopy or fine-needle aspiration is frequently used to make the histologic diagnosis. Patients with NSCLC who have enlarged mediastinal lymph nodes should undergo mediastinoscopy or bronchoscopic transbronchial biopsy to determine resectability (mediastinal nodes are rarely resectable). If an adrenal gland is enlarged, biopsy of the adrenal gland should be performed. In patients with resectable disease, surgical treatment may offer a chance for cure. Positron-emission tomography (PET) is a useful test during the work-up of the patient with NSCLC, but positive findings require pathologic or more precise radiologic corroboration before deciding against lung cancer surgery.

Small Cell Lung Cancer The goal of staging in SCLC is to determine which patients have limited-stage disease (about 30% to 40% of SCLC patients at the time of diagnosis) who can be potentially cured by the administration of combined chemoradiotherapy, compared with patients with extensive-stage metastatic

disease who cannot be cured but who can enjoy significant palliation with extension of survival as a result of chemotherapy. Limited-stage SCLC is defined as regional intra thoracic disease that can be encompassed within a single radiation field. Conversely, extensive disease represents locally advanced or widely metastatic disease that extends beyond a reasonable radiation field. Because common sites of metastatic disease include brain, liver, bone, and adrenal glands, diagnostic tests are performed to target these areas. The staging system for each type of lung cancer is shown in Table 57-2. For the patient with NSCLC, tumor size, proximity to central structures, and location of lymph nodes are the most important features. Because surgery is rarely performed for the patient with SCLC, nodal detail is seldom obtained. The regional extent of the cancer and the ability to encompass the involved areas within a single radiation field determine treatment planning (Table 57-3).

TREATMENT Non–Small Cell Lung Cancer Because complete removal of the tumor provides the best chance for long-term survival, the focus of the primary treat-

Chapter 57—Solid Tumors

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Table 57-3 Treatment and Outcomes for Lung Cancer Tumor

Standard Treatment by Stage

Outcome

Non–small cell lung cancer

Early stages: surgery only (I); surgery followed by adjuvant chemotherapy (II, IIIA)

Small cell lung cancer

Later stage (unresectable): Combined chemotherapy and radiation or chemotherapy alone Limited: cisplatin-based chemotherapy with concurrent chest radiation Prophylactic cranial radiation is considered Extensive: chemotherapy palliates symptoms and prolongs survival but is not curative

Early stages: patients with stage II lung cancer have a 40%-50% survival rate with surgery and adjuvant chemotherapy Late stage: patients with stage IV lung cancer have 1-yr survival rate near 20% with chemotherapy Limited: 20%-30% 5-yr survival rate

ment for the patient with NSCLC should begin with an assessment of resectability. Resectability depends on the anatomic location of the tumor as well as the patient’s medical condition and pulmonary reserve. In general terms, the risk for pneumonectomy is small if the patient has a forced expiratory volume in 1 second greater than 2 L, carbon dioxide diffusing capacity of more than 60%, a maximal voluntary ventilation of more than 50% of predicted values, or the ability to walk up three flights of stairs. Lesser resections (e.g., lobectomy) may require less stringent criteria. Occasionally, patients with severe obstructive disease cannot undergo a curative procedure because they lack pulmonary reserve. Patients with stage I and II tumors (localized lesions or involvement limited to hilar lymph nodes) should undergo surgical treatment. Peripheral tumors are removed by lobectomy; more central tumors, if resectable, may require pneumonectomy. Stage III tumors may be operable in some patients, particularly if they are treated with chemotherapy and radiation therapy (i.e., neoadjuvant therapy) before resection. In patients with significant mediastinal lymph node involvement detected during tumor resection or at the time of mediastinoscopy, the chance of longterm survival is less than 20% even with surgical treatment. Although postoperative radiation therapy is seldom useful, recent reports show a survival benefit when patients with stages II and IIIA undergo adjuvant chemotherapy. Chemotherapy using a variety of agents combined with cisplatin or carboplatin improves survival after surgery by about 5%. Almost 80% of lung cancers are unresectable. If the tumor cannot be resected and has not spread to distant organs (stages IIIA and IIIB), chemotherapy is administered concurrently with radiation. This treatment leads to better median survival and 5-year disease-free survival rates than with radiation alone, but combined therapy for unresectable disease should be reserved for patients with good functional status. Aggressive treatment is much less effective (due to unacceptable toxicity) in patients who have lost more than 5% of their body weight or who are active less than 50% of the day. The median survival for patients with locally advanced, unresectable lung cancer who are candidates for combined modality therapy is now 15 to 18 months, and nearly 20% achieve a 5-year disease-free survival. Patients with metastatic disease may benefit from chemotherapy. The most active agents are platinum derivatives

Extensive: median survival rate is 10 mo with treatment

such as cisplatin and carboplatin, taxanes such as paclitaxel and docetaxel, gemcitabine, vinorelbine, irinotecan, and pemetrexed. About 20% to 30% of patients achieve a greater than 50% reduction in their tumor volume after chemotherapy. For patients with advanced-stage lung cancer (stages IIIB with pleural effusion and IV), chemotherapy improves survival from an average of 8.5 to 11 months; quality-of-life studies show that chemotherapy delays symptoms and reduces their severity compared with no treatment. New agents that target neoplastic angiogenesis such as bevacizumab or the epidermal growth factor receptor antagonists such as erlotinib and cetuximab have shown therapeutic benefit either as single agents (e.g., erlotinib) or, more commonly, in combination with chemotherapy (bevacizumab) for these cancers.

Small Cell Lung Cancer Patients with limited-stage SCLC are treated with curative intent with combined (concurrent) modality chemotherapy and radiotherapy. It is common practice to treat these patients with four to six cycles of chemotherapy (most commonly with cisplatin or carboplatin and etoposide) along with radiation therapy delivered to a radiation field encompassing the intrathoracic disease. About 50% to 60% of patients experience a complete response, and another 20% to 30% have a partial shrinkage of their cancer. Because 50% to 60% of patients with SCLC will ultimately develop brain metastases, prophylactic cranial radiation should be considered for those patients who have a complete response in the lung to primary chemoradiotherapy. About 20% to 30% of treated patients with limited-stage SCLC are alive and free of disease 3 years after diagnosis, and a proportion of these individuals are cured. Although patients with extensivestage SCLC cannot be cured with existing therapy, chemotherapy can cause rapid tumor shrinkage with resolution of symptoms resulting in significant prolongation of life compared with supportive care alone.

Recurrent Lung Cancer Both NSCLC and SCLC have high relapse rates. The use of second-line chemotherapy for these patients may palliate symptoms, but its use is not curative. Although these cancers may respond to subsequent agents such as docetaxel, pemetrexed, and erlotinib (NSCLC) or the camptothecins, the taxanes, and oral etoposide (SCLC), the use of these drugs should be limited to patients with good performance status, preferably on a clinical trial.

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Section X—Oncologic Disease

Head and Neck Cancers EPIDEMIOLOGY AND NATURAL HISTORY Most cancers of the head and neck, including cancers of the larynx, oral cavity, oropharynx, and sinuses, are squamous cell carcinomas. In 2008, an estimated 35,310 new cases were diagnosed, and 7590 deaths occurred. Tobacco use, alcohol consumption, and poor oral hygiene have all been linked to the development of cancers of the head and neck. Nasopharyngeal cancers are associated with Epstein-Barr viral infection. Infection with human papillomavirus (HPV), in particular HPV-16, is now an established risk factor for oropharyngeal cancer. The major determinant of prognosis is the tumor burden, or the thickness of the tumor, and the presence or absence of regional lymph node involvement. The cure rate with small tumors is as high as 75% to 95% with radiation therapy or surgery. Continued use of tobacco after a diagnosis of a head and neck cancer is associated with a poor prognosis. People who have had cancer of the head and neck are at high risk for having a primary lung or esophageal cancer.

SYMPTOMS Symptoms of cancers of the head and neck are related to the location of the tumor. For example, supraglottic laryngeal cancers cause pain with swallowing and a change in voice quality. Cancers of the oral cavity may exhibit a mass under the tongue or red or white patches in the mouth. Bleeding in the mouth or ill-fitting dentures may also be symptoms of cancer in the oral cavity. Symptoms of cancers of the sinus include sinusitis that does not resolve with appropriate treatment. Ear pain may be present with cancers of the oropharynx or hypopharynx.

DIAGNOSIS

may also derive palliative benefit from combined modality chemotherapy (or cetuximab) and radiotherapy.

Gastrointestinal Cancers Cancers of the gastrointestinal tract are among the most common tumors, with more than 271,000 new cases occurring in 2008. Advances in the treatment of colorectal cancer have improved survival and quality of life for patients with these diseases. Table 57-4 outlines the common signs and symptoms, treatments, and prognosis of gastrointestinal tumors.

ESOPHAGEAL CANCER Epidemiology and Natural History The two types of esophageal cancer are squamous cell and adenocarcinoma. Squamous cell cancers are most common in the cervical and thoracic esophagus, and adenocarcinomas commonly occur in the lower esophagus down to the gastroesophageal junction. Squamous cell cancers are more common in African Americans and are associated with predisposing factors that include smoking, caustic injury, achalasia, and alcohol intake. Squamous cell cancers are associated with other tobacco-related cancers in the upper airways and digestive tract. The rate of adenocarcinoma is increasing; this increase is related in part to Barrett esophagus, an adenomatous metaplasia of the distal esophagus often caused by gastroesophageal reflux disease, but other factors are likely. Almost 25% of patients with severe Barrett esophagus eventually develop esophageal adenocarcinoma. The most useful intervention for patients with Barrett esophagus is frequent endoscopic screening and biopsy; pharmacologic treatment of acid reflux disease does not prevent neoplastic transformation.

Diagnosis of head and neck cancers require histologic confirmation with biopsy. Magnetic resonance imaging (MRI) or a CT scan of the head and neck is performed to determine a precise estimate of the extent of the tumor. Thorough examination of the entire aerodigestive tract with endoscopy will demonstrate a synchronous second primary tumor, for example, in the esophagus, in up to 15% of patients. Staging of the tumor is based on clinical and radiographic assessment.

Symptoms

TREATMENT

An upper gastrointestinal radiographic series or endoscopy will demonstrate an esophageal lesion, which should then undergo biopsy. The most effective staging tool is endoscopic ultrasonography, an accurate tool in assessing local depth of penetration and lymph node metastases. CT and positron-emission tomographic (PET) scanning are also required to ensure that the tumor has not already metastasized to the chest or liver, the two most common sites of spread.

Small tumors that have not spread to regional lymph nodes are treated with radiation or surgery. Primary radiation therapy may allow preservation of organ function of, for example, the larynx, with surgical resection used in the case of recurrence. Locally advanced disease is treated with a combination of surgery and radiation therapy (with or without chemotherapy), or with a combination of radiation therapy and cisplatin-containing chemotherapy regimens. Most relapses occur within 2 to 3 years after therapy. Close surveillance is therefore warranted. Good-performance status patients with locally advanced, unresectable disease

The most common symptom of esophageal cancer is dysphagia. As the lumen of the esophagus narrows, the patient loses normal swallowing capacity and has a sensation that solid food becomes “stuck.” Eventually, the patient may be unable to swallow liquids. Patients commonly become afraid to eat because of frequent regurgitation at mealtime, resulting in significant weight loss.

Diagnosis

Treatment The most common treatment of esophageal cancer is surgery. Resection of the involved esophagus includes a wide margin


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Table 57-4 Gastrointestinal Cancers Tumor Site

Common Findings

Standard Treatments

Expected Outcome

Esophageal

Dysphagia, chest pain, weight loss

Stage II/III stage: about 30% 5-yr survival Average survival for metastatic disease is 90% 5-yr survival Positive nodal involvement: 20%-75% 5-yr survival for tumors 70% at 5 yr Nodal involvement: 50%-70% at 5 yr Metastatic: median 14-24 mo

Localized: 70% at 5 yr

posing conditions include pernicious anemia, achlorhydria, gastric ulcers, and prior gastric surgery. Except for cancers of the gastroesophageal junction, gastric cancer rates have decreased in the United States (21,500 new cases occurring in 2008). A recognized risk factor for gastric cancer is infection with Helicobacter pylori. Whether early treatment of H. pylori infection changes the rate of cancer in infected populations is not clear.

Diagnosis Patients with gastric cancer commonly experience abdominal pain, early satiety, anemia, hematemesis, weakness, and weight loss. Frequently, the cancer has already involved local lymph nodes by the time the diagnosis is made. Physical examination may show a gastric mass, an umbilical node (Sister Mary Joseph node), or a left supraclavicular node (Virchow node). Pathologic analysis shows an adenocarcinoma that can be localized or spread throughout the gastric lining (linitis plastica). Required staging includes a CT scan to search for obvious nodal or metastatic involvement of the liver, upper gastrointestinal endoscopic examination, and endoscopic ultrasonography to determine depth of invasion and biopsy abnormal lymph nodes.

Treatment Gastric cancer is most often treated surgically. When the tumor and all relevant lymph nodes have been removed, patients have a 20% to 60% chance of a 5-year survival, depending on the pathologic stage. If gastric cancer recurs,

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the most common sites are local extension or hematogenous spread through the portal vein to the liver. Patients undergoing a complete resection for gastric cancer benefit from the addition of 5-fluorouracil (5-FU) and leucovorin chemotherapy and postoperative radiation therapy. This combination improves median survival by about 15 months compared with no adjuvant therapy. Patients with metastatic gastric cancer may elect chemotherapy to palliate symptoms. Active agents include platinum compounds, fluoropyrimidines, anthracyclines, taxanes, and irinotecan. Combination chemotherapy provides a 20% to 40% response rate and may extend survival.

COLORECTAL CANCER Epidemiology and Natural History About 1 in 20 people in the United States will be diagnosed with colon cancer (lifetime risk is 6%). An estimated 148,700 new cases were diagnosed in 2008, and in the same year, nearly 50,000 deaths occurred. Known predisposing factors are a history of ulcerative colitis and a strong family history of colon cancer. Several mutations, whether inherited or spontaneous, play a major role in the predisposition to colon cancer (see Chapter 55, Fig. 55-1 and Table 55-2). For example, familial polyposis is transmitted in an autosomal dominant manner. Individuals have mutations in the APC gene, which may be associated with periampullary and thyroid cancers or non-neoplastic growth such as osteomas, sebaceous cysts, and gastric polyps. Hereditary nonpolyposis colorectal cancer (HNPCC) is a more common autosomal disorder associated with microsatellite instability and mutations in hMSH-2, hMLH-1, PMS-1, PMS-2, and hMSH-6. Patients with HNPCC usually have colon or endometrial cancer when younger than 50 years and have first-degree relatives with colon cancer or other HNPCC-related cancers derived from the stomach, ovary, small bowel, biliary tract, ureter, or renal pelvis. Whether the predisposing risk for colon cancer is genetically transmitted or sporadically acquired, a clear relationship exists between adenomatous polyps and the later development of colon cancer. Because the removal of polyps is probably the most important way to prevent the development of invasive colon cancer, the most reliable way to reduce colon and rectal cancer mortality is to perform regular screening. Colonoscopy is the most commonly used screening test. Studies using sigmoidoscopy and regular fecal occult blood testing also show reductions in the incidence and mortality of colorectal cancer. Patients with a proven mutation (Gardner syndrome, HNPCC) or a strong family history (familial adenomatous polyposis), and those who acquire other diseases associated with colorectal cancer, such as ulcerative colitis, should begin colonoscopy earlier than suggested for the general population. For patients with familial adenomatous polyposis, screening should start in the teenage years. For patients with HNPCC, screening for colon cancer should start 10 years before the age of diagnosis in the youngest family member with colorectal cancer. Research efforts are underway in the primary prevention of colorectal cancers using interventions such as diet, daily aspirin, cyclo-oxygenase-2 inhibitors, calcium and vitamin D supplementation, and other chemopreventive agents to reduce cancer incidence. Enthusiasm for promoting a high-

fiber diet to reduce the risk for colon cancer has waned. Lifestyle changes are still considered important—fresh fruits and vegetables, regular exercise, fewer than two red meat servings per week—based on epidemiologic association.

Symptoms Rectal bleeding commonly occurs with colon and rectal cancers. Patients with left-sided colon lesions often complain of a change in stool color or caliber or pelvic pain and transient bloating. Right-sided lesions may become friable and may result in occult bleeding. Occasionally, patients with colon and rectal cancers are asymptomatic until the tumor totally obstructs the bowel or perforates the peritoneal cavity. Colon and rectal cancers tend to spread hematogenously to the lungs and liver. Rectal cancer is more likely than colon cancer to recur locally because it is more difficult to get a wide margin of normal tissue and lymph nodes within the tight confines of the pelvis.

Diagnosis The work-up for colon cancer requires measurement of serum carcinoembryonic antigen (CEA), an abdominalpelvic CT scan, a chest radiograph, and endoscopic imaging of the colon to ensure that all polyps and cancers are removed near the time of the primary operation. Table 57-5 describes the staging system for colon and rectal cancers.

Treatment In patients with stages I, II, and III colon cancer, surgical resection of the primary carcinoma along with any regional lymph node metastases is routinely performed; multiagent, adjuvant chemotherapy is recommended for all patients with stage III cancer (which reduces the rate of recurrence by about 40%) and for selected high-risk individuals with stage II cancer. For patients with rectal cancer, either primary resection (which may require colostomy) or neoadjuvant chemoradiotherapy is performed. Because of the higher likelihood of local recurrence in rectal cancer, any lesion that invades the muscle or lymph nodes is also treated with radiation therapy (if not given before surgery) and adjuvant chemotherapy. Surgical resection of the primary lesion in patients with advanced (stage IV) colorectal cancer

Table 57-5 Staging for Colon and Rectal Cancer Stage

Tumor Size

Nodal Status

Metastases

0 I

In situ Invades mucosa only May invade muscularis or through serosa Any size tumor or any level of invasion Any size or depth

No No

No No

No

No

Yes

No

Positive nodal involvement present or absent

Yes

II

III IV

Chapter 57—Solid Tumors may be recommended to palliate or avoid symptoms of obstruction, bleeding, and pain. Significant advances have been made in the use of chemotherapy for colorectal cancer. Regimens proved successful in prolonging survival for colon cancer include 5-FU with leucovorin or its oral analogue, capecitabine, alone. The addition of oxiliplatin to 5-FU–based adjuvant therapy has recently been shown to further improve survival after surgery. In the setting of metastatic cancer, infusions of chemotherapy with FOLFOX (5-FU, leucovorin, oxiliplatin), or FOLFIRI (5-FU, leucovorin, irinotecan) with the addition of antibodies targeting the vascular endothelial growth factor (VEGF; bevacizumab) or the epidermal growth factor receptor (cetuximab) prolong median survival beyond 20 months, almost twice the survival expected in the early 1990s. Despite improvements in survival, metastatic colon and rectal cancers are incurable unless the metastatic lesions can be surgically resected.

ANAL CARCINOMA Anal cancers are increasing in frequency (currently about 5000 new cases per year). Persons infected with HPV and HIV are more likely to develop anal cancer. Patients with anal cancer usually experience rectal bleeding or complain of rectal fullness. Combined chemotherapy with 5-FU and mitomycin and radiation therapy make up the standard approach to a patient with localized anal cancer. Results with combined therapy are superior to those with surgery, with the additional benefit of sparing the anal sphincter. Abdominoperineal resection is reserved for patients in whom chemoradiotherapy fails.

PANCREATIC CANCER Epidemiology and Natural History Pancreatic cancer, which is diagnosed in more than 37,000 people living in the U.S. each year, is strongly associated with cigarette smoking. A small proportion of pancreatic cancers are inherited from mutations in the p16 and BRCA-2 genes. Epithelial pancreatic cancer is an adenocarcinoma with an extremely high mortality rate because it is usually diagnosed when the tumor is beyond the capability of surgical resection. A less common type of pancreatic cancer, islet cell carcinoma, originates in the endocrine cells. Symptoms related to secretion of peptides such as gastrin, vasointestinal polypeptide, and insulin characterize these tumors.

Symptoms The most common presentation of epithelial pancreatic cancer is abdominal pain accompanied by rapid weight loss. Characteristically, the pain is located in the periumbilical region and pierces or stabs through to the back. The pain is often explained by the frequent invasion of the celiac plexus deep in the retroperitoneum. Other symptoms of pancreatic cancer are the recent onset of diabetes, intestinal angina reflecting encasement of the superior mesenteric artery, a palpable gallbladder (Courvoisier sign), and jaundice from blockage of the distal common bile duct. Migrating thrombophlebitis (Trousseau sign) is a paraneoplastic complication of pancreatic adenocarcinoma. The tumor

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marker CA-19-9 is elevated in up to 75% of patients with pancreatic cancer.

Treatment The only curative treatment for pancreatic cancer is pancreaticoduodenectomy (Whipple procedure), an extensive operation requiring three anastomoses that carries a high mortality rate in centers with less experience with the procedure. The 5-year survival for surgically treated patients with localized pancreatic cancer is 25% for node-negative cancer but only 10% when lymph nodes are involved. Accordingly, it has become standard practice to offer adjuvant chemoradiotherapy or gemcitabine chemotherapy alone, which may provide a survival advantage. Patients with unresectable disease may benefit from local radiation therapy with concurrent 5-FU; more than 30% of patients treated with this combination have some improvement in their symptoms. Alternatively, gemcitabine-based chemotherapy alone may have palliative benefit. When patients have progressive or metastatic disease, the use of palliative chemotherapy with weekly gemcitabine has been shown to improve quality of life and survival to a small degree (5.7 months with gemcitabine, 4.4 months without gemcitabine, or 20% 1-year survival versus 5%). Recent meta-analyses suggest that certain gemcitabine-based chemotherapy combinations offer limited survival advantage over gemcitabine alone.

HEPATOCELLULAR CARCINOMA Although uncommon in the United States (about 21,000 new cases per year), hepatocellular carcinoma (HCC) is one of the most common cancers throughout the world; more than 1 million cases are diagnosed each year. The common causes of HCC are chronic viral hepatitis (both B and C) and cirrhosis related to alcohol use or hemochromatosis. Although this approach is unproved, considerable interest exists in screening patients who are at extremely high risk with serial measurement for α-fetoprotein (AFP) levels. AFP levels are commonly elevated even in early-stage HCC. Treatment of early-stage HCC is surgery. Cure rates are more than 75% for patients with tumors smaller than 2 cm. Patients with severe cirrhosis and who have small liver cancers may benefit from liver transplantation. Chemoembolization may provide palliative benefit for patients with unresectable tumors, but conventional cytotoxic chemotherapy is generally ineffective. However, recent findings suggest that molecularly targeted tyrosine kinase inhibitors such as sorafenib offer a survival advantage over supportive care.

Breast Cancer EPIDEMIOLOGY Breast cancer is the most common nonskin cancer in women and the second leading cause of cancer death (after lung cancer) among women in the United States. In 2008, an estimated 182,460 women were diagnosed with invasive breast cancer, and more than 40,000 died from breast cancer. Breast cancer in men is rare. Risk factors for breast cancer include older age, a family history of breast cancer, early menarche, late menopause,

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first-term pregnancy after age 25 years, nulliparity, prolonged use of exogenous estrogen, and postmenopausal obesity. Exposure to ionizing radiation, as is used in the treatment of Hodgkin disease, also increases the risk for breast cancer. Only 5% to 10% of patients with breast cancer are associated with the breast cancer-susceptibility genes, BRCA-1 and BRCA-2. Patients with multiple affected family members or those with a personal or family history of male breast cancer, bilateral breast cancer, or ovarian cancer should be offered genetic counseling and genetic testing for BRCA-1 and BRCA-2. Mammographic screening in both average- and high-risk populations has been shown to reduce breast cancer mortality.

PATHOLOGY Most breast cancers are infiltrating ductal adenocarcinomas. A smaller proportion of breast cancers are infiltrating lobular adenocarcinomas. Tubular and mucinous carcinomas, which are a subtype of infiltrating ductal cancers, are associated with a better prognosis. The estrogen and progesterone receptor status of the primary tumor should be assessed in all cases of invasive breast cancer. The oncoproteinoncogene HER-2/neu (human epidermal growth factor receptor) is important in defining prognosis and treatment. Tumors that are negative for the estrogen and progesterone receptor and for overamplification of the HER-2 oncogene (i.e., the so-called triple-negative tumors) are associated with a poorer prognosis. Such tumors are characteristic of those that develop in women who have the BRCA-1 breast cancer susceptibility gene. Ductal carcinoma in situ (DCIS), also called intraductal carcinoma, is increasing in frequency, most likely because of increased mammographic screening.

CLINICAL PRESENTATION Breast cancer is most often diagnosed through screening mammography or after a patient or her physician notices a palpable mass. Fewer than 10% of women have metastatic disease at diagnosis. Recurrent breast cancer most commonly exhibits metastases in the bone, liver, lung, and central nervous system, but breast cancer can recur in any organ of the body. Women with a history of breast cancer are also at increased risk for breast cancer in the contralateral breast. Inflammatory breast cancer is a clinical diagnosis in a woman with breast induration and erythema, often without a palpable mass. The skin findings are due to tumor emboli in the dermal lymphatics; skin biopsy is negative for cancer in 50% of patients.

STAGING Breast cancer staging requires removal of the primary tumor and ipsilateral axillary lymph node assessment. Women with tumors larger than 5 cm and those with positive axillary lymph node involvement may have additional radiographic tests, including a chest radiograph, bone scan, and CT scan of the abdomen. Patients with smaller tumors and negative lymph node involvement do not need these tests unless they exhibit symptoms (e.g., skeletal pain) suggestive of metastatic involvement.

TREATMENT For women with small breast tumors, breast-conserving therapy with lumpectomy followed by radiation therapy is standard therapy. Women with large tumors or with two or more tumors in separate quadrants of the breast should undergo mastectomy. Some women who are candidates for breast-conserving therapy choose to have a mastectomy, with or without breast reconstruction. Women who have had previous radiation to the breast, either for a previous breast cancer or other malignancies, are generally treated with mastectomy. Chemotherapy administered before surgical treatment (primary or neoadjuvant chemotherapy) may allow breast conservation in women with large tumors who would otherwise not be able to undergo a lumpectomy. Preoperative hormone therapy can be considered in frail patients with hormone receptor–positive tumors, but hormone therapy does not replace surgical treatment for most patients. Adjuvant therapy with chemotherapy and hormonal therapy improves relapse-free and overall survival rates in premenopausal and postmenopausal women who are at high risk for metastatic relapse. The monoclonal antibody trastuzumab, directed at the HER-2 pathway, improves disease-free survival in patients with tumors that have overamplification (or high levels of overexpression) of the HER-2 oncoprotein. Treatment decisions in women with metastatic disease are based on the hormone receptor status, sites of disease, presence and severity of symptoms, time since initial diagnosis, and previous treatments. The monoclonal antibody trastuzumab may be used in combination with chemotherapy, hormonal therapy, or as a single agent. Life expectancy is longer in women with hormone-responsive disease and with lymph node or bone metastases, rather than liver, lung, or central nervous system metastases. Patients with metastatic breast cancer may live for many years, often responding to hormonal therapy for years before requiring chemotherapy for disease control. Many chemotherapeutic agents (singly or in combination), including the anthracyclines, taxanes, alkylating agents, fluoropyrimidines, vinca alkaloids, gemcitabine, and epithilones, demonstrate activity against breast cancer. Bisphosphonates, such as zoledronate and pamidronate, are given intravenously to decrease the pain associated with bone metastases and the risk for fracture in women with skeletal metastases. DCIS is treated with either lumpectomy followed by radiation therapy or mastectomy. Women with multifocal or palpable DCIS should have assessment of lymph node status because a small but measurable proportion will have positive lymph node involvement that suggests the presence of invasive cancer. In these patients, systemic treatment is identical to that given to women with a clearly invasive breast primary tumor. Prophylactic bilateral mastectomy is offered to women with the BRCA-1 or BRCA-2 breast cancer susceptibility genes. An alternative approach is close clinical surveillance, including monthly self-examination, frequent examination by a physician, and regular mammography or MRI. Oophorectomy or antiestrogen therapy can be used to decrease the risk for breast cancer in these women and in other women at high risk for the disease (see Chapter 56).


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Table 57-6 Genitourinary Cancers Tumor Site Testicle

Prostate

Bladder

Renal cell

Common Findings

Standard Treatments

Expected Outcomes

Testicular swelling, pain, back pain Cough with metastatic presentation Elevated prostatespecific antigen, decreased urinary stream Bone pain with metastatic presentation Hematuria, cystitis

Inguinal (not scrotal) orchiectomy Node-positive seminoma: radiation therapy Node-positive NSGCT: RPLND or chemotherapy

Early-stage seminoma: >90% 5-yr survival Stage III NSGCT: about 75% 5-yr survival Poor-risk tumors: 35 inches in women), glucose intolerance (fasting plasma glucose ≥100 mg/dL), hypertension (≥130/≥85 mm Hg), elevated plasma triglycerides (≥150 mg/dL), and low high-density lipoprotein (HDL) cholesterol (50% PMN

Reactive arthritis (Reiter syndrome) Spondyloarthropathy

Young to middle-aged men

Axial skeleton, pelvis (sacroiliac joints)

Systemic lupus erythematosus

Women in childbearing years

Hands, knees

PMN, neutrophils; SF, synovial fluid; WBC, white blood cells.

SF: High WBC, >90% PMN, culture Noninflammatory SF

SF: Low-to-moderate WBC, almost 100% have antinuclear antibodies

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Muscle

Section XVI—Musculoskeletal and Connective Tissue Disease

Bursa

Joint space

Synovial membrane

Tendon

Muscle inflammation (Myositis)

Bursa

Joint space: joint infection

Synovial membrane: Synovitis (Rheumatoid arthritis) Tendon

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Enthesis

Periosteum Bony end plate

Joint Cartilage capsule

Joint space

Periosteum Bony end plate (Avascular necrosis)

Joint capsule

Enthesis: Enthesopathy (Ankylosing spondylitis)

Cartilage: Cartilage Joint space: degeneration Microcrystalline (Osteoarthritis) arthritis (Gout) Figure 78-1 Anatomic structures of the musculoskeletal system (left). Location of musculoskeletal disease processes (right). (From Gordon DA: Approach to the patient with musculoskeletal disease. In Bennett JC, Plum F [eds]: Cecil Textbook of Medicine, 20th ed. Philadelphia, WB Saunders, 1996, p 1440.)

neuropathy as seen in many vasculitides), and central nervous system disease (SLE and vasculitis). Recurrent miscarriages, livedo reticularis, Raynaud phenomenon, and recurrent thrombotic events are suspicious for antiphospholipid antibody syndrome (primary or secondary to SLE). At the initial evaluation, one important question is whether diagnosis and treatment of the patient’s problem require urgent attention. Infectious processes obviously belong in this category. The presence of acute joint inflammation, fever, and systemic signs such as chills, night sweats, and leukocytosis all provide supporting evidence for infection. Gouty arthritis may share some or all of these clinical features, but its onset tends to be more abrupt. Inflammation extending beyond the margins of the joint is characteristic of septic arthritis and is otherwise seen only in crystal disease and rheumatoid arthritis. Nonarticular processes— cellulitis, septic bursitis, tenosynovitis, and phlebitis—may mimic infectious arthritis. Analysis of synovial fluid is the key to diagnosis. Acute nerve entrapment or spinal cord compression, tendon rupture, and fractures may all occur in the absence of obvious trauma. Spinal cord compression may be the result of a herniated disk or vertebral subluxation. Tendon rupture may occur in inflammatory arthritides, particularly in the wrist in rheumatoid arthritis. Pelvic and other insufficiency fractures may be seen in patients with osteoporosis or osteomalacia. Careful musculoskeletal and neurologic examinations help in the detection of these disorders, each of which requires urgent treatment. In systemic rheumatic diseases, the onset is usually more insidious, and the clinical course is prolonged. Treatment is usually less urgent and can be safely deferred, particularly if the diagnosis is uncertain. However, potential threats to life or the possibility of serious and/or irreversible organ damage may exist in some disorders. In SLE and systemic vasculitis, patients may have central or peripheral nervous system disease, including brain and peripheral nerve infarcts, glomerulonephritis, inflammatory or hemorrhagic lung disease, coronary artery involvement, intestinal infarcts, and digital infarcts. Threatened digital loss may also be seen in sclero-

derma and Raynaud’s disease. Renal crisis may occur in scleroderma, with vasculopathy leading to renal infarcts, azotemia, micro-angiopathy, and severe hypertension. Urgent therapy to ameliorate or prevent damage may be indicated in these disorders. In giant-cell arteritis, acute blindness is a potential complication, and the diagnosis requires urgent therapy even before confirmatory biopsy. Acute inflammatory myositis should be promptly treated because it may progress rapidly to the involvement of the respiratory musculature. In some cases, major organ involvement may be occult. When systemic disease is suggested, the patient’s lung and kidneys should be carefully evaluated.

Laboratory Testing As noted earlier, synovial fluid analysis is an important part of the evaluation of arthritis (Table 78-3). It helps distinguish inflammatory from noninflammatory arthritis and can be diagnostic of infectious arthritis or crystal disease. Synovial fluid consists of an ultrafiltrate of plasma into which synovial lining cells secrete hyaluronic acid, which is responsible for the high viscosity of synovial fluid. Evaluation of synovial fluid should include the following: (1) cell count and differential, (2) crystal examination for sodium urate and calcium phosphate dehydrate crystals, and (3) Gram stain and culture. Synovial fluid glucose and protein are not diagnostically useful tests. Synovial fluid examination should be performed in the evaluation of all acute arthritides and all situations in which joint infection is probable and ideally should be performed on at least one occasion in the evaluation of chronic inflammatory arthritis. Aspiration and analysis of fluid before therapy are critical to appropriate decision making. Although autoantibodies are often considered the hallmark of rheumatic diseases, their diagnostic utility in individual patients is actually much less than commonly believed. Although almost 100% of patients with SLE have antinuclear antibodies, as do most patients with scleroderma and autoimmune myositis, the proportion of patients with positive

Chapter 78—Approach to the Patient with Rheumatic Disease

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Table 78-3 Classification of Synovial Effusions by Synovial White Cell Count Group Normal I. Noninflammatory II. Mildly inflammatory III. Severely inflammatory (noninfectious) IV. Severely inflammatory (infectious)

Diagnosis (Examples)

Appearance

Synovial Fluid White Cell Count (mm3)*

Polymorphonuclear Cells (%)

Osteoarthritis; trauma Systemic lupus erythematosus Gout Pseudogout Rheumatoid arthritis Bacterial infections

Clear, pale yellow Clear to slightly turbid Clear to slightly turbid Turbid Turbid Turbid Very turbid

0-200 50-2000 (600)

20%) as opposed to the lower concordance among other siblings (90%), can also be the most debilitating. One should exclude other reasons for fatigue, including anemia, hypothyroidism, and fibromyalgia. Malignancy should also be suspected if lymphadenopathy persists (see later).

MUCOCUTANEOUS Oral ulcerations may be painful or painless and are classically located on the tongue or palate. Skin manifestations of SLE are protean and include the classic malar (butterfly) rash, discoid lesions (permanent scarring and disfigurement), alopecia, and photosensitivity.

MUSCULOSKELETAL Arthralgias and inflammatory arthritis are common manifestations in lupus (>75%). The arthritis of lupus is usually nonerosive (as opposed to rheumatoid arthritis), but a subset of patients (10%) have Jaccoud arthropathy with reversible hand deformities secondary to inflammation and joint laxity.

CARDIOPULMONARY More than 60% of lupus patients have pericarditis and pleuritis during their disease course. Subsequent pericardial or pleural effusions are typically exudative, with low normal glucose levels. Valvular thickening and noninfective Libman-Sacks endocarditis are frequently observed on echocardiography and autopsy studies. Myocarditis should be suspected in patients with cardiopulmonary symptoms and fever. Pulmonary hemorrhage is a rare and potentially catastrophic manifestation of SLE that may result in fulminant hemoptysis and respiratory failure. Premature CVD in lupus is described later.

RENAL Nephritis is a major cause of morbidity and mortality in lupus patients. It can manifest with hematuria and/or proteinuria, and the clinical spectrum of glomerulopathies is classified by the World Health Organization (Class I to VI). Class IV (diffuse, proliferative) lupus nephritis has the worst prognosis but is also the most amenable to aggressive systemic therapy

NEUROPSYCHIATRIC Neuropsychiatric symptoms are broad, including sensori motor neuropathy, headache, cognitive dysfunction, anxiety,

Leukopenia, primarily lymphopenia, anemia, and thrombocytopenia are very common in SLE patients. Anemia is secondary to hemolysis or chronic disease. Antiphospholipid and anticardiolipin antibodies are present in one third of lupus patients and are associated with multiple thromboses, thrombocytopenia, and recurrent spontaneous miscarriages (see Chapter 78).

VASCULAR Over 40% of all lupus patients have Raynaud phenomenon. Venous (pulmonary emboli, deep venous thrombosis) and arterial clots are typically secondary to antiphospholipid and anticardiolipin antibodies. Small vessel vasculopathy or vasculitis can occur in any organ system (neurologic, gastrointestinal) and can be life threatening.

OCULAR Keratoconjunctivitis sicca from secondary Sjögren syn drome (see Chapter 86) is the most common ocular manifestation of SLE. Episcleritis, scleritis, and retinal vasculitis are rare.

Diagnosis SLE is a clinical diagnosis; no single test or feature is definitively diagnostic of the disease. Many patients’ clinical disease evolves over time, and only after several years (and several different visits to physicians) are patients recognized as having SLE. Criteria for the classification of SLE were established to more accurately conduct lupus research studies (Table 81-2). Although these classification criteria are not meant to be diagnostic, practicing clinicians can use them, with a comprehensive examination, as a guide to help diagnose SLE. One must always consider other rheumatic diseases (rheumatoid arthritis, Sjögren syndrome), infections (endocarditis, hepatitis), and malignancy in the differential diagnosis of SLE. Various autoantibodies are found in patients with SLE and are the hallmark laboratory feature of the disease (Table 81-3). These autoantibodies are often present before the onset of SLE clinical manifestations. Virtually all patients with SLE (>95%) test positive for antinuclear antibodies. Although many of the specific antigens to which these antinuclear antibodies are directed have been determined and are useful both diagnostically and clinically in SLE, some antibodies are also seen in other autoimmune diseases. Antibodies to double-stranded DNA and the Smith antigen are highly specific for lupus, whereas antibodies to SSA/Ro and SSB/La antigens are also commonly found in patients with Sjögren syndrome and rheumatoid arthritis. Certain antibodies are associated with specific clinical manifestations of disease, particularly anti–double-stranded DNA antibodies with lupus nephritis. Autoantibodies alone are not

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Table 81-1 Clinical Manifestations of Systemic Lupus Erythematosus Cardiac Pericarditis* Pericardial effusion Myocarditis Valvular thickening Libman-Sacks endocarditis Atherosclerotic heart disease Constitutional ss

Fatigue Fever Lymphadenopathy Weight loss Anorexia Gastrointestinal Hypomotility Mesenteric vasculitis Malabsorption Protein-losing gastroenteropathy Lupus enteropathy Thrombosis of mesenteric and hepatic vasculature Hepatitis Hepatomegaly Splenomegaly Pancreatitis Acalculous cholecystitis Peritonitis Hematologic Leukopenia* Lymphopenia* Hemolytic anemia* Nonhemolytic anemia (anemia of chronic disease, irondeficiency anemia) Thrombocytopenia* Antiphospholipid antibody syndrome Mucocutaneous Oral, genital, nasal ulcers* Angioedema Alopecia Photosensitivity* Malar (butterfly) rash* Discoid lesions* Subacute cutaneous lupus Tumidus Panniculitis Vasculitis Chilblain Urticaria Periungual erythema

Table 81-1 Clinical Manifestations of Systemic Lupus Erythematosus —cont’d Neuropsychiatric Seizures* Cerebritis, aseptic meningitis Cerebrovascular disease Transverse myelitis Chorea Headache Cognitive impairment Autonomic dysfunction Cranial neuropathy Peripheral neuropathy Psychosis* Anxiety Depression Mood disorder Ocular Keratoconjunctivitis sicca Episcleritis Scleritis Retinal vasculitis Arterial and venous occlusions Optic neuritis Pulmonary Pleuritis* Pleural effusion Pneumonitis Alveolar hemorrhage Interstitial lung disease Bronchiolitis obliterans Pulmonary hypertension Pulmonary emboli Vasculitis Acute reversible hypoxemic syndrome Shrinking lung syndrome Renal Cellular casts or glomerulonephritis* Proteinuria or membranous nephropathy or nephrotic syndrome* Reproductive Recurrent spontaneous abortions Premature fetal delivery Neonatal lupus Serologic Abnormalities Autoantibodies* Hypocomplementemia Elevated acute phase reactants

Musculoskeletal

Vascular

Arthritis* Arthralgias Jaccoud arthropathy Avascular necrosis Myositis

Raynaud phenomenon Livedo reticularis Arterial or venous thrombosis Vasculitis (almost any location)

diagnostic for any autoimmune disease but must be interpreted in the clinical context.

Clinical Subsets Some patients with autoimmune symptoms have clinical and laboratory features of two or more specific autoimmune

*An item in the American College of Rheumatology diagnostic criteria.

diseases and are considered to have an overlap syndrome. Mixed connective tissue disease is characterized by overlaps among SLE, scleroderma, and myositis with a high titer of anti-U1 RNP antibody levels. For patients who have a few autoimmune manifestations but do not yet meet criteria of a specific autoimmune disease, the term undifferentiated connective tissue disease is used. These patients typically are

Chapter 81—Systemic Lupus Erythematosus

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Table 81-2 Updated Criteria for Classification of Systemic Lupus Erythematosus* Criterion 1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Arthritis 6. Serositis

7. Renal disorder 8. Neurologic disorder

9. Hematologic disorder

10. Immunologic disorder

11. Antinuclear antibody

Definition Fixed erythema, flat or raised, is observed over the malar eminences, tending to spare the nasolabial folds. Erythematous raised patches develop with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions. Skin rash occurs as a result of unusual reaction to sunlight by patient history or physician observation. Oral or nasopharyngeal ulceration, usually painless, is observed by the physician. Nonerosive arthritis involves two or more peripheral joints, characterized by tenderness, swelling, or effusion. a. Pleuritis: Convincing history of pleuritic pain exists, or rub is heard by a physician, or pleural effusion is in evidence. OR b. Pericarditis: Is documented by electrocardiogram or rub or evidence of pericardial effusion. a. Persistent proteinuria is >0.5 g/day or >3+ if quantitation is not performed. OR b. Cellular casts: May be red cell, hemoglobin, granular, tubular, or mixed. a. Seizures: Occur in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, electrolyte imbalance) OR b. Psychosis: Occurs in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, electrolyte imbalance) a. Hemolytic anemia: Develops with reticulocytosis. b. Leukopenia: 6.5 mg/kg, and obesity. Patients should have baseline and annual ophthalmologic examinations with visual field testing. Azathioprine and methotrexate are both immunosuppressive agents prescribed in patients with lupus either when glucocorticoids alone are not fully effective or to allow for a reduction in the glucocorticoid dose. Toxicities of azathioprine include cytopenias, increased infection risk, and potential association of hematologic malignant disease (controversial). Azathioprine may be used during pregnancy for severe internal organ lupus (especially nephritis). Methotrexate is particularly effective with inflammatory arthritis associated with lupus. In addition to cytopenias and infections, liver function abnormalities, alopecia, nausea, and pneumonitis are potentially seen with methotrexate. Because it is teratogenic, methotrexate should be stopped 3 to 6 months before pregnancy. Both drugs require monthly laboratory monitoring. Mycophenolate mofetil (MMF) is increasingly used to treat patients with internal organ involvement of lupus, particularly nephritis. MMF inhibits purine synthesis of lymphocytes and has been standard treatment in the prevention of solid-organ transplant rejection. Recent clinical trials have shown that MMF is as efficacious as intravenous (IV) cyclophosphamide (described later) for inducing remission of active lupus nephritis. Toxicity of MMF includes gastroin-

testinal disturbance and leukopenia; it also has a category D rating in pregnancy. Patients with neurologic lupus, rapidly progressive nephritis, or vasculitis of internal organ systems are often treated with cyclophosphamide, the most potent immunosuppressive agent (alkylating agent) used to treat SLE. Because it is extremely toxic, this drug is generally reserved for the most severe disease manifestations of lupus. In a series of studies, primarily conducted at the National Institutes of Health, monthly IV cyclophosphamide was effective in reducing the rate of progression of lupus nephritis to endstage renal disease. Acute toxicities of cyclophosphamide include pancytopenia, alopecia, mucositis, and hemorrhagic cystitis. Long-term cyclophosphamide use may lead to transitional cell carcinoma, hematologic malignant disease, sterility, premature menopause, and opportunistic infections. Many other treatments have been used in SLE, although extensive clinical trials demonstrating efficacy are lacking. Among these drugs, intravenous immunoglobulin may be effective for SLE-related thrombocytopenia and catastrophic antiphospholipid syndrome. Thrombotic thrombocytopenic purpura secondary to SLE may be treated with plasmapheresis. Immunoablation with high-dose cyclophosphamide with or without autologous stem cell transplant has been tried in a small number of patients with progressive active disease that is refractory to conventional immunosuppressive therapy; unfortunately mortality is high, and data are preliminary. Great potential and optimism exist for “biologic” immunomodulating agents that focus on various aspects of the immune system, including B cells, interactions between B and T cells, and cytokines. The most promising current therapeutic agents are those that deplete B cells, producers of autoantibodies. Among these, rituximab has been successfully used in refractory lupus patients with hematologic and renal disease manifestations.

Special Issues in the Care of Patients with Systemic Lupus Erythematosus PREGNANCY Pregnant women with lupus have higher rates of both pregnancy loss (miscarriage and stillbirth) and preterm delivery (premature rupture of membranes, preeclampsia, and intrauterine growth restriction). Lupus activity preceding conception, especially nephritis, hypertension, and antiphospholipid antibody syndrome, are clear risk factors for pregnancy complications in SLE. Pregnancy itself may place women with lupus at greater risk for a flare, particularly if the disease, specifically nephritis, was active before conception. Neonatal lupus is a rare disorder in which maternal antiSSA/Ro-SSB/La antibodies cross the placenta and injure the fetus. Mothers with these autoantibodies have a 2% risk of having a child with congenital heart block (CHB). These mothers are screened with fetal heart tones and fetal echocardiography between weeks 16 and 34 of gestation. Treatment with a fluorinated corticosteroid (dexamethasone)

Chapter 81—Systemic Lupus Erythematosus may be beneficial; however, a considerable number of children with CHB do not survive (30%) or experience morbidity, with over 60% requiring pacemakers. More common manifestations of neonatal lupus are skin rashes, cytopenias, and hepatosplenomegaly, all of which resolve within 6 to 8 months (after maternal autoantibodies are removed from the child’s circulation). Mothers of children with neonatal lupus do not necessarily have SLE or Sjögren syndrome; however, some of these women eventually are diagnosed with an autoimmune disease. With careful prenatal screening and planning, women with lupus can successfully have a healthy child. Prenatal monitoring of anti-SSA/Ro-SSB/La antibodies and antiphospholipid and anticardiolipin antibodies and a prepregnancy high-risk obstetric consultation are critical. Ideally, women with lupus should have clinical quiescence for 6 months before considering a planned pregnancy. Special consideration must also be given to medications, as the majority of immunosuppressants (methotrexate, mycophenolate mofetil, and cyclophosphamide) are teratogenic.

HORMONAL THERAPY Hormones are thought to play a role in the development of SLE, given its female predominance. Consequently, rheumatologists have historically been hesitant to prescribe estrogen therapy for fear of inducing a flare. Recently, randomized, placebo-controlled clinical trials, described in the next paragraphs, have helped to guide hormonal therapy in women with lupus. A multicenter randomized trial revealed that oral contraceptive therapy does not appear to increase the risk of SLE flares in women with mild or stable SLE disease activity. However, this is not generalizable to all women with SLE, in particular those whose disease is active or severe and those with prior thrombotic events or antiphospholipid and anticardiolipin antibodies. Clearly, an effective form of birth control is necessary for young sexually active women with SLE, especially those taking teratogenic medications. Physicians must carefully discuss the risks and benefits of birth control with lupus patients. Hormone replacement therapy (HRT) is a controversial topic, regardless of lupus status. However, it is of particular interest in SLE because some women with lupus reach menopause prematurely. In a recent clinical trial of HRT in SLE patients with mild or stable disease, with no prior thrombotic events, antiphospholipid and anticardiolipin antibodies, or malignancies of women, no lupus patients had severe clinical flares, but 20% did have mild to moderate flares. These findings suggest that brief (1 year) HRT may have a role in alleviating menopausal symptoms or in treating osteoporosis in a certain subset of women with SLE.

CARDIOVASCULAR DISEASE As survival and therapies for lupus have improved, CVD has emerged as a leading cause of morbidity and mortality. Lupus patients are 5 to 10 times more likely than healthy individuals to have a coronary event. More striking, premenopausal women aged 35 to 44 are more than 50 times as likely as healthy women to experience a myocardial infarc-

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tion. Autopsy series have revealed atherosclerotic heart disease as the underlying mechanism of CVD in SLE. The cause of this premature atherosclerosis in lupus is multifactorial and includes inflammatory mediators, lupus-related factors (premature menopause, corticosteroid therapy, disease activity), and traditional cardiovascular risk factors. Prevention of CVD is a critical aspect of the care of lupus patients. Although no firm CV management guidelines exist for SLE patients, many argue that lupus patients should be considered and treated as coronary heart disease riskequivalents. Cardiac disease must be thought of and aggressively evaluated in SLE patients with both typical and atypical cardiac symptoms, regardless of age.

MALIGNANCY Recently, a multicenter international cohort of nearly 10,000 lupus patients reported an increased risk of malignancy in SLE compared with the general population. Most striking was a threefold to fourfold increased risk of non-Hodgkin lymphoma. Other hematologic, lung, and hepatobiliary cancers were also described with increased frequency in SLE patients. Malignancy risk appears to be highest early in the disease course, but malignancy is clearly a risk throughout a patient’s life span. Older age, tobacco use, SLE disease damage, and immunosuppressant use appear to be associated with cancers in SLE; however, the exact mechanism of malignancy in SLE is not yet fully elucidated. Although lymph node enlargement is a common manifestation in lupus patients, physicians must have a high index of suspicion for malignancy if the lymphadenopathy does not resolve with lupus treatment, is tender or nonmobile, or occurs without other lupus symptoms.

BONE HEALTH Lupus patients have higher rates of low bone mineral density (BMD), osteoporosis, and fractures, than do healthy agematched subjects. The increased risk is accounted for by both traditional risk factors, such as female sex, white race, older age, and low body weight, and lupus-associated factors. Fatigue and articular symptoms secondary to SLE may limit physical activity, leading to loss of bone strength. Furthermore, therapies commonly used in lupus contribute to overall loss of bone health. Corticosteroids reduce bone mass and are an independent risk factor for fractures in women with SLE. Cyclophosphamide use can lead to premature ovarian failure, another risk factor for osteoporosis. In addition, lupus disease damage, regardless of steroid use, leads to low BMD, suggesting that SLE itself is a risk factor for low BMD. Another contributing factor may be that lupus patients are commonly asked to avoid sun exposure, which can lead to low vitamin D levels and insufficient absorption of calcium. Given these SLE-specific risk factors for low BMD, prevention of osteoporosis is extremely important. Although osteoporosis screening guidelines for SLE patients are the same as for the general population, bone density scans should also be considered in patients with premature menopause and those who are or who will be on chronic (>3 months) corticosteroids.

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Prospectus for the Future • Advances in the understanding of the immunopathologic features of SLE, providing a logical framework for specific targeting and testing of new biologic therapies. • Clinical trial data to evaluate the efficacy of new biologic agents for the treatment of SLE.

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References Arbuckle MR, McClain MT, Rubertone MV, et al: Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349:1526-1533, 2003. Austin HA 3rd, Klippel JH, Balow JE, et al: Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 314:614-619, 1986. Bernatsky S, Boivin JF, Joseph L, et al: An international cohort study of cancer in systemic lupus erythematosus. Arthritis Rheum 52:1481-1490, 2005. Buyon J, Petri, MA, Kim MY, et al: The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med 142:953-962, 2005. Domsic RT, Ramsey-Goldman R, Manzi S: Epidemiology and classification of SLE. In: Hochberg MC, Silman AJ, Smolen JS, et al (eds): Rheumatology, 4th ed. Philadelphia, Mosby, 2008.

• Development of formal management guidelines for osteoporosis and cardiovascular care in patients with SLE.

Ginzler EM, Dooley MA, Aranow C, et al: Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 353:2219-2228, 2005. Lee C, Almagor O, Dunlop DD, et al: Disease damage and low bone mineral density: An analysis of women with systemic lupus erythematosus ever and never receiving corticosteroids. Rheumatology (Oxford) 45:53-60, 2006. Lee C, Ramsey-Goldman R: Bone health and systemic lupus erythematosus. Curr Rheumatol Rep 7:482-489, 2005. Manzi S, Meilahn EN, Rairie JE, et al: Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 145:408-415, 1997. Petri M, Kim MY, Kalunian KC, et al: Combined contraceptives in women with systemic lupus erythematosus. N Engl J Med 353:2550-2558, 2005.

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XVI

Antiphospholipid Antibody Syndrome

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Surabhi Agarwal and Amy H. Kao

A

ntiphospholipid antibody syndrome (APS) is a disorder characterized by recurrent vascular thrombosis and/or recurrent pregnancy loss in the presence of positive antiphospholipid (aPL) antibodies. The aPL antibodies were initially identified in patients with falsepositive syphilis screening test results (positive result in the absence of syphilis). Lupus anticoagulant (LAC) was later described in patients with systemic lupus erythematosus (SLE), which was also frequently associated with a falsepositive result of a screening test for syphilis and was paradoxically associated with thrombosis and recurrent pregnancy loss. LAC is a misnomer because this in vitro anticoagulant effect reflects the prolonged activated partial thromboplastin time (aPTT), and the presence of LAC does not indicate a diagnosis of lupus. Furthermore, both LAC and anticardiolipin (aCL) antibodies were shown to bind to phospholipid-binding plasma proteins and not directly to phospholipids.

Pathogenesis Animal studies suggest that aPL may be directly pathogenic. The linear correlation between antibody levels and risk of thrombosis further supports their pathogenic role. aPL can cause β2-glycoprotein I (β2-GPI)–dependent endothelial activation by upregulation of expression of adhesion molecules and secretion of proinflammatory cytokines. β2-GPI interferes with Von Willebrand factor–dependent platelet activation; neutralization of this effect by β2-GPI antibodies may also potentiate the risk of thrombosis. aPL also induces platelet activation, leading to increased platelet adhesion and thromboxane synthesis. In addition, aPL may confer acquired resistance to the anticoagulant properties of protein C and annexin A5, further contributing to the increased risk of thrombosis. aPL displaces annexin A5 from the trophoblastic surface, which may contribute to pregnancy loss. Important to note, aPL-mediated thrombosis and fetal loss are complement-dependent, and heparin therapy acts via

complement inhibition rather than as an anticoagulant as previously believed.

Clinical Features A subset of people with aPL antibodies eventually exhibit manifestations of APS. Both arterial and venous thrombosis may occur in vessels of any size. Venous thrombosis, especially of the lower extremities, is by far the most common manifestation. Up to half of affected patients develop associated pulmonary embolism. The most common site of arterial thrombosis is the central nervous system, with manifestations including seizures, stroke, dementia, and psychosis. Transverse myelitis, chorea, and Guillain-Barré syndrome have also been reported. In addition, microthrombotic disease is being recognized as a manifestation of APS. Renal failure may occur as a result of microthrombosis and renal artery thrombosis. Cardiac valve thickening (Libman-Sacks endocarditis) is frequently found in patients with APS. These noninfectious vegetations may be a source of embolism. Any valve can be affected, with mitral regurgitation being the most frequent hemodynamic abnormality, followed by aortic regurgitation. This is frequently asymptomatic; and the need for surgery is uncommon. Unlike rheumatic heart disease and bacterial endocarditis, valvular thickening is diffuse and rarely causes rupture. A major feature of APS is recurrent pregnancy loss, especially after the 10th week of gestation. Fetal distress, intrauterine growth retardation, premature births, uteroplacental insufficiency, and oligohydramnios contribute to major pregnancy morbidity. Preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) are also frequent complications. Other prominent manifestations of APS include mild thrombocytopenia, with platelet count usually above 50,000/ mL; APS seldom causes hemorrhage. Hemolytic anemia is relatively uncommon and may occur simultaneously with thrombocytopenia (Evans syndrome). Livedo reticularis 841

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may often be noted on physical examination of patients with APS. Leg ulcers, gangrene, thrombophlebitis, nailfold infarcts, cutaneous necrosis, and necrotizing purpura may be seen. The term catastrophic APS (CAPS) has been coined to describe patients who exhibit multiple microthromboses, positive aPL antibodies, and often a life-threatening illness resulting in multi-organ failure that can be clinically indistinguishable from sepsis or thrombotic thrombocytopenic purpura. Although the precise cause of CAPS remains unclear, preceding infection has been reported in multiple cases and is thought to be a precipitating factor.

Diagnosis The classification criteria of APS are shown in Table 82-1. The presence of clinical features with laboratory evidence of aPL antibodies is necessary to establish the diagnosis of APS. In addition, the patient should repeat testing for aPL antibodies at least 12 weeks apart using the same laboratory because transient elevation can be seen with

Table 82-1 Revised Classification Criteria of Antiphospholipid Syndrome Antiphospholipid antibody syndrome (APS) is present if at least one clinical criterion and one laboratory criterion are met. Clinical Criteria 1. Vascular thrombosis: One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (i.e., unequivocal findings of appropriate imaging studies or histopathology). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall. 2. Pregnancy morbidity (a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus OR (b) One or more premature births of a morphologically normal neonate before the 34th week of gestation because of (i) eclampsia or severe preeclampsia; (ii) recognized features of placental insufficiency OR (c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded. Laboratory Criteria 1. Lupus anticoagulant (LAC) present in plasma on two or more occasions at least 12 weeks apart. 2. Anticardiolipin (aCL) antibody of immunoglobulin G (IgG) and/or IgM isotype in serum or plasma, present in medium or high titer (i.e., >40 GPL or greater than the 99th percentile), on two or more occasions at least 12 weeks apart, measured by a standardized enzyme-linked immunosorbent assay (ELISA). 3. Anti–β2-glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma (in titer greater than the 99th percentile) present on two or more occasions at least 12 weeks apart, measured by a standardized ELISA.

infections, malignancies, medications, and other autoimmune diseases. APS is considered primary if it occurs in isolation and secondary if it occurs in conjunction with other autoimmune diseases such as SLE. There are no major differences in severity or clinical consequences between primary and secondary APS. Progression from primary APS to SLE is unusual. The reported prevalence of various aPL antibodies in SLE ranges from 16% to 55%. Patients with SLE who have aPL antibodies not only have an increased risk of thromboembolism and pregnancy complications but are also found to have a higher prevalence of pulmonary hypertension, Libman-Sacks endocarditis, and neurologic complications (seizures, strokes, and transverse myelitis). As mentioned previously in this chapter, aPL antibody assays detect a heterogeneous group of antibodies that bind serum proteins such as β2-GPI, prothrombin, cardiolipin, annexin A5, and other negatively charged phospholipids. The assays that are useful clinically include LAC, aCL, and β2-GPI antibodies. Various methods, such as the Russell viper venom time, aPTT, kaolin clotting time, and hexagonal lipid neutralization test, are used to test for LAC. Anticoagulation therapy may interfere with these assays. The presence of LAC is the strongest predictor of thrombosis among aPL antibodies. The immunoglobulin (Ig) isotypes of aCL antibodies may be IgG, IgM, or IgA. The specificity of these antibodies for APS increases with higher titer and is the highest with the IgG isotype.

Management Currently, treatment for APS is tailored to the patient and the associated clinical manifestations. For patients with vascular thrombosis, indefinite anticoagulation is usually prescribed as prophylaxis against recurrence. Warfarin is the usual drug of choice for long-term therapy, with a target of international normalized ratio (INR) between 2 and 3. Higher INR level (3 to 4) is not more effective and is associated with bleeding complications. Unfractionated and low– molecular-weight heparin is also an effective anticoagulant for APS patients and is used in patients who experience recurrent events while on warfarin therapy or in patients who are or plan to become pregnant. Treatment in patients with persistently elevated aPL antibody levels without thrombosis has not been well established and is not clearly indicated. Low-dose aspirin (75 to 100 mg) has been considered a logical option, but its efficacy has not been substantiated by prospective studies. Hydroxychloroquine, an antimalarial drug commonly used in SLE, may be protective against the development of thrombosis by reducing the binding of aPL–β2-GPI complexes to phospholipid bilayers. Risk factor modification, including avoidance of oral contraceptives and hormonal therapy, smoking cessation, and aggressive management of dyslipidemia, hypertension, and diabetes, should always be considered in these patients. Anticoagulation prophylaxis should be also considered in high-risk situations, such as surgery and prolonged immobilization. Risk of recurrent pregnancy loss in APS can be reduced with combination treatment of low-dose aspirin and heparin. Intravenous immunoglobulin (IVIG) and plasmapheresis

Chapter 82—Antiphospholipid Antibody Syndrome have been used with mixed results in refractory cases. Warfarin should be switched to therapeutic doses of heparin before and during pregnancy because of the teratogenic effects of warfarin. Pregnancy in APS patients is considered high risk and requires a team approach with careful monitoring by the obstetrician and hematologist. Corticosteroids and immunosuppression have a minimal role in management of thrombosis in APS except in CAPS.

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Although there are no randomized controlled trials for treatment of CAPS, combinations of corticosteroids, anticoagulation, and/or plasmapheresis have been used. Evidence to support the use of cyclophosphamide has been documented mainly in patients with SLE with CAPS. Infections have been identified as a major precipitating factor for initiation of CAPS cascade; hence infection must be treated aggressively in these patients.

Prospectus for the Future • Large cohort studies may provide data for better risk stratification and targeted prophylactic therapy.

References Asherson RA, Cervera R, Piette JC, et al: Catastrophic antiphospholipid syndrome: Clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore) 80:355-377, 2001. Del Papa N, Guidali L, Sala A, et al: Endothelial cells as target for antiphospholipid antibodies. Human polyclonal and monoclonal anti-beta 2-glycoprotein I antibodies react in vitro with endothelial cells through adherent beta 2-glycoprotein I and induce endothelial activation. Arthritis Rheum 40:551-561, 1997. Finazzi G, Marchioli R, Brancaccio V, et al: A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 3:848-853, 2005. Galli M, Luciani D, Bertolini G, Barbui T: Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: A systematic review of the literature. Blood 101:1827-1832, 2003.

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• Complement inhibition may be a potential novel therapy in the treatment of recurrent pregnancy loss in patients with APS. However, further studies are warranted.

Holers VM, Girardi G, Mo L, et al: Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med 195:211-220, 2002. Lellouche F, Martinuzzo M, Said P, et al: Imbalance of thromboxane/prostacyclin biosynthesis in patients with lupus anticoagulant. Blood 78:2894-2899, 1991. Merkel PA, Chang Y, Pierangeli SS, et al: The prevalence and clinical associations of anticardiolipin antibodies in a large inception cohort of patients with connective tissue diseases. Am J Med 101:576-583, 1996. Miyakis S, Lockshin MD, Atsumi T, et al: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4:295-306, 2006. Nojima J, Kuratsune H, Suehisa E, et al: Acquired activated protein C resistance associated with IgG antibodies against beta2-glycoprotein I and prothrombin as a strong risk factor for venous thromboembolism. Clin Chem. 51:545-552, 2005. Rand JH, Wu XX, Quinn AS, et al: Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid bilayers. Blood 112:1687-1695, 2008.

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83

Systemic Sclerosis (Scleroderma) Robyn T. Domsic and Thomas A. Medsger, Jr.

T

he hallmark of systemic sclerosis (SSc) is cutaneous and visceral fibrosis, which is reflected in the other common term for the disease, scleroderma, which derives from the Greek scleros, meaning thick, and derma, referring to skin. The disorder can range from a relatively benign condition to a rapidly progressive disease leading to significant morbidity or death. Although cutaneous manifestations are the most obvious, it is the visceral involvement that can be the most severe or disabling. Awareness of and monitoring for potential organ complications are essential in caring for patients with SSc, as early detection and treatment of complications minimize morbidity and mortality.

Epidemiology The annual incidence of SSc in the United States is approximately 20 cases per million persons. As many patients with SSc live for many years, the prevalence is 240 cases per million. The incidence and prevalence varies somewhat throughout the world and is generally lower in Europe and Asia. SSc more commonly affects women, with a 3 : 1 female:male ratio. It occurs in individuals of all ages, from childhood to the elderly, but is most frequent in the fourth through seventh decades. The familial pattern of inheritance is not as evident in SSc as in other rheumatic diseases, although many patients with SSc have family histories of autoimmune thyroid disease, rheumatoid arthritis, and lupus. Twin studies have demonstrated a 5% rate of concordance in both monozygotic and dizygotic twins, suggesting that both genetics and environment contribute to its occurrence.

Pathologic Considerations The pathogenesis of SSc is complex and has not been fully elucidated. However, there are three clear components: (1) 844

fibrosis with overproduction of collagen and other connective tissue matrix proteins, (2) vascular injury and obliteration, and (3) immune system activation (Fig. 83-1). The involvement of all three of these systems initially became evident from autopsy examinations. Examination of the skin reveals thickening of the dermis with excessive deposition of collagen fibrils, and fibrous replacement of subcutaneous fat and secondary skin appendages such as hair follicles and sebaceous glands. Vascular changes include endothelial cell injury and subintimal thickening leading to luminal narrowing with occasional vascular occlusion. Periadventitial fibrosis is frequent. The vascular changes are seen in the skin but also may occur in the pulmonary, cardiac, and renal systems and involve arteries, arterioles, and capillaries. Cutaneous inflammatory infiltrates consist of activated mononuclear cells, T lymphocytes, and monocytes in the dermis, often in a perivascular distribution. True vasculitis is conspicuously absent. The interplay among the vascular, connective tissue, and immunologic changes is complex. Fibroblasts are found in increased numbers in the skin and other tissues, live longer, and produce an overabundance of collagen. Although fibroblasts can be activated by the immune system in normal skin repair, cultured skin fibroblasts have a persistent SSc phenotype, suggesting an abnormality not requiring continued immune stimulation. Other potential factors may contribute to fibrosis, including hypoxia and local cytokine changes. Endothelial cell activation with resultant leukocyte migration, smooth muscle cell proliferation, and matrix deposition have been implicated in the vascular changes. In the serum, increased levels of inflammatory markers (sedimentation rate) and circulating cytokines are seen. More than 95% of patients with SSc have one of nine serum autoantibodies relatively specific to scleroderma, all of which are directed at distinct antigens. These antibodies are helpful in classifying patients, but to date, their pathogenic role has not been elucidated.

Chapter 83—Systemic Sclerosis (Scleroderma) Immune cell homing

Vascular injury and proliferation

IL-4 PDGF

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Endothelin TGF-β

IL-1 ss

Accumulation of interstitial matrix Figure 83-1 Pathogenetic processes in systemic sclerosis. Vascular injury leads to intimal proliferation of both endothelial cells (red) and smooth muscle cells (blue). Fibroblasts are activated to deposit increased amounts of interstitial matrix. IL, interleukin; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β.

Clinical Features SKIN CLASSIFICATION SSc is separated into two major clinical subsets, diffuse cutaneous and limited cutaneous sclerosis, defined by the degree and extent of skin involvement. Patients with limited cutaneous involvement experience skin thickening limited to the extremities (below the elbows and knees). Patients with diffuse cutaneous SSc have similar distal changes and also involvement of the upper arms, thighs, or trunk at some time during the disease course. A small proportion of patients (50,000 WBCs/mL) and more than 90% PMNs. Polarized light microscopic examination of synovial fluid is the key to diagnosis. Intracellular, needle-shaped, negatively birefringent crystals are both pathognomonic for, and essential to, the definitive diagnosis of acute gouty arthritis (Fig. 87-3). Viewed under polarized light with a red compensator, urate crystals are yellow when parallel to the compensator axis and blue when perpendicular. Crystals may range in length from 1 to 2 µm to 15 to 20 µm, appearing similar to a lance that has pierced the neutrophil (colloquially referred to as the “martini glass” sign). Extracellular crystals of typical size and shape are supportive, but not diagnostic,

Chapter 87—Crystal Arthropathies

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A

B

MSU CPPD Figure 87-3 Polarized microscopy of (A) strongly negative birefringent monosodium urate crystals and (B) weakly positive CPPD crystals. Arrows indicate axis of polarization. (A, Adapted from the ACR Slide Collection on the Rheumatic Diseases; B, adapted from Saadeh C, Malacara JC: Calcium Pyrophosphate Deposition Disease. Available at: http://www.emedicine.com/med/topic1938. htm, May 4, 2006.)

of acute gouty arthritis. Urate crystals may also be seen in the white toothpaste-like material obtained from tophaceous deposits and occasionally from a joint into which a tophus has ruptured. In 5% to 10% of gouty arthritis cases, crystals are not isolated from the affected joint. In other instances, particularly in small joints such as the MTP joint, synovial fluid may be difficult to aspirate. In a patient with known gout, a presumptive diagnosis is reasonable unless clinical features suggest septic arthritis. As previously indicated, serum uric acid is not a useful diagnostic screen, given that many patients have normal levels at the time of an acute attack and that elevated levels of uric acid are found in a high proportion of individuals lacking clinical manifestations of gout. Radiographs may show tophi or typical juxta-articular, “rat bite” erosions with sclerotic borders and overhanging edges (Martel sign). Mild peripheral blood leukocytosis, elevated erythrocyte sedimentation rate, and increased acute phase proteins may be seen but are entirely nonspecific.

Table 87-2 Treatment of Acute Gout Drug

Route

Side Effects

Colchicine

PO IV

NSAIDs

PO

Glucocorticoids

PO, IV, IM Intra-articular

Diarrhea, cramps Bone marrow failure, neuromyopathy Gastritis, bleeding, renal insufficiency Increased blood sugar Mask infection

IM, intramuscular; IV, intravenous; NSAIDs, nonsteroidal anti- inflammatory drugs; PO, oral.

achieved. Individuals who overproduce and overexcrete uric acid are at risk for developing renal stones; in general, those eliminating greater than 700 mg/day of urinary uric are at risk. Stones may be composed of uric acid, or uric acid may form a nidus for calcium and other types of stones.

CHRONIC POLYARTICULAR GOUT AND EXTRA-ARTICULAR MONOSODIUM URATE DEPOSITION

TREATMENT

Gout may evolve into a chronic polyarthritis with or without acute attacks of arthritis. Patients with this form of gout often have multiple juxta-articular tophi and can develop destructive, erosive joint disease. Occasionally, polyarticular gout may appear similar to rheumatoid arthritis, and tophi may be mistaken for rheumatoid nodules. As indicated earlier, radiographs in chronic gout typically show sclerotic changes at erosive borders in a juxta-articular distribution, contrasting with the peri-articular, nonsclerotic, marginal erosions characteristic of rheumatoid arthritis. Synovial fluid analysis is diagnostic, justifying the examination of synovial fluid for crystals in patients with polyarthritis. When significant monosodium urate crystal deposition does occur in the body, visible tophi may be present. Tophi most commonly form adjacent to joints, in bursae, on extensor surfaces of tendons, and, less commonly, on cartilaginous structures such as the pinnae of the ear. In severe cases, deposition may occur in other tissues, including the renal interstitium, where higher concentrations of uric acid are

A variety of treatments are effective for acute gouty arthritis (Table 87-2). Joint drainage per se has a therapeutic effect in removing degenerating PMNs and in relieving joint distension. Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective when adequate anti-inflammatory doses are used and are often the first drug of choice; however, NSAIDs should be avoided in patients with renal insufficiency, a common association with gout. Colchicine prevents the release of PMN chemotactic factors and inhibits phospholipase activation, which is needed for prostaglandin synthesis. This medication is particularly effective early in a gout attack, resulting in rapid resolution of symptoms, but is much less effective after 24 hours. Colchicine can be given by repeated dosing every 1 to 2 hours with a strict total dose limit of 6 mg. However, the practice of using hourly administration until abdominal cramps or diarrhea supervene is to be discouraged. Intravenous colchicine is effective and rapid in onset of effect but must be used with extreme caution, particularly in the setting of hepatic or renal dysfunction. Given reported cases of fatal arrhythmia and bone marrow

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failure associated with use of intravenous colchicine, its use has been largely abandoned. Alternatives to NSAIDs and colchicine include intra-articular glucocorticoids that have a rapid onset of action and are almost free of side effects. If the diagnosis of gout is fairly certain, various preparations of glucocorticoids may be instilled at the time of joint aspiration. Oral glucocorticoids in moderate-to-high doses may also be used; however, in patients with underlying diabetes or glucose intolerance, hyperglycemia may ensue. Nonetheless, in many patients with other comorbid medical conditions such as peptic ulcer disease and renal insufficiency, systemic glucocorticoids may be the best treatment option for acute gout. Parenteral adrenocorticotropic hormone and parenteral glucocorticoids are both effective treatments but are more costly. To prevent recurrent attacks after an acute attack of gout, colchicine prophylaxis for several weeks is a reasonable treatment option (see later discussion).

Intercritical and Chronic Gout After a single attack of gout, the physician must decide whether to recommend long-term therapy. A substantial number of patients will have rare attacks, even if left untreated, leaving little rationale for immediate institution of lifelong therapy. On the other hand, patients with very high levels of serum uric acid or whose first attack occurs at a young age are at greatest risk of frequent attacks and subsequent development of chronic gouty arthritis, tophaceous gout, and/or destructive joint disease. If patients do have frequent recurrent attacks, then prophylactic treatment is advised (Table 87-3). In patients with mild gout and occasional attacks, prophylaxis with colchicine alone may be sufficient. However, in patients who have renal stones, tophi, erosive joint disease, polyarticular disease, or frequent, recurrent attacks of gout despite risk factor modification and prophylactic use of colchicine, long-term uric acid–lowering therapy is clearly indicated. The choice of agent depends (in part) on whether the patient overproduces uric acid or fails to efficiently eliminate this biochemical byproduct, a determination that rests on assessment of 24-hour urinary uric acid excretion occurring with a low-purine diet. Uric acid–lowering agents fall into two general categories—uricosurics and xanthine oxidase inhibitors. Theoretically, uricosurics should be most commonly employed based on the distribution of uric acid underexcretion (90%) versus overproduction (10%) in the setting of gout. Probenecid, the prototypical uricosuric used in the United States, inhibits urate reabsorption in the distal tubule and promotes excretion. However, the effectiveness of probenecid hinges on intact renal function (glomerular filtration rate [GFR] >50 mL/min), and use of this medication may be impractical in many patients because of the requirement for increased fluid intake needed to prevent uric acid crystal formation in the renal tubules or urinary tract. Therefore, in patients who cannot tolerate probenecid or already have urate nephropathy or nephrolithiasis, allopurinol is a more appropriate choice. Allopurinol inhibits xanthine oxidase, the enzyme that catalyzes the formation of xanthine from hypoxanthine and uric acid from xanthine. It is effective in lowering the levels of uric acid whether they result from impaired clearance or from overproduction. Allopurinol, although generally safe, has greater toxicity than probenecid and has

Table 87-3 Treatment of Intercritical Gout Drug Colchicine

NSAIDs

Probenecid

Allopurinol

Mechanism of Action Destabilizes microtubules Inhibits neutrophil chemotaxis, adhesion, and phagocytosis No effect on uric acid Inhibit cyclo-oxygenase No effect on uric acid Uricosuric No anti-inflammatory activity Inhibits uric acid synthesis

Side Effects Very safe (low dose); rare neuromyopathy

Peptic ulcer disease, renal insufficiency Very safe

Dermatitis, hepatitis, interstitial nephritis, marrow failure

NSAIDs, nonsteroidal anti-inflammatory drugs.

been associated with a severe hypersensitivity syndrome characterized by acute interstitial nephritis, hepatitis, and severe skin reactions. Recent studies suggest that febuxostat, a nonpurine inhibitor of xanthine oxidase, may be a potential alternative for patients with hyperuricemia and gout who are intolerant of allopurinol. Once the decision is made to institute allopurinol or probenecid, concomitant colchicine prophylaxis should be initiated and continued for several months. Allopurinol, in particular, can precipitate gouty attacks when first administered, presumably because of the rapid lowering of uric acid levels that mobilizes tissue deposits and facilitates shedding of preformed crystals. For this reason, neither allopurinol nor probenecid should be started in the setting of an acute attack. In patients with persistent, chronic arthritis despite urate-lowering therapy, chronic use of nonsteroidal agents (other than aspirin) may be required for the control of pain and inflammation. Occasionally, surgical removal of tophi may be beneficial, particularly in locations where they become irritated, inflamed, or infected. Although dietary modification is recommended as an adjunct to pharmacologic therapy, dietary purine intake accounts for a relatively small proportion of daily uric acid turnover. Therefore little clinical effect will likely occur from drastic dietary alterations. Nevertheless, anchovies, sweetbreads, organ meats, and cellular leafy vegetables such as spinach are particularly high in purines and should be excluded from the diet. Most importantly, alcohol should be avoided because of its dual impact on uric acid overproduction and impairment of renal tubular function.

Asymptomatic Hyperuricemia In patients who are to receive chemotherapy, short-term prophylaxis with allopurinol may prevent both gout and renotubular precipitation of uric acid. Newer agents, including intravenous pegylated uricase, are also helpful in preventing the “tumor lysis” syndrome. Beyond this clinical situation, the significance of “asymptomatic” hyperuricemia

Chapter 87—Crystal Arthropathies has been the subject of detailed investigation based on associations with hypertension, renal dysfunction, cardiovascular disease, and the metabolic syndrome. Although a number of clinico-epidemiologic studies, animal models, and in vitro experimental systems collectively provide a compelling case that hyperuricemia is an independent risk factor for vascular endothelial and smooth muscle dysfunction, routine treatment of asymptomatic hyperuricemia is not currently recommended.

Calcium Pyrophosphate Dihydrate Deposition Disease CPPD deposition disease results from the formation of CPPD crystals in articular cartilage and fibrocartilage as well as other periarticular structures. Such deposits are common and increase in incidence with advancing age, affecting over 30% of individuals older than 80 years of age. In most individuals with CPPD deposition, an asymptomatic radiographic finding termed chondrocalcinosis is observed. Typical areas of involvement include the menisci of the knee, the triangular fibrocartilage of the wrist, and the symphysis pubis. Articular cartilage may be involved anywhere, but the knee, wrist, and ankle are the most commonly affected sites. Acute goutlike attacks of arthritis may result when crystals are shed from such deposits, particularly when these crystals are bound by opsonins such as immunoglobulin G (IgG); hence, the disease is often called pseudogout. In middle-aged women, a chronic, smoldering polyarthritis may be associated with CPPD deposition. Referred to as chronic pyrophosphate arthropathy, this entity has clinical and radiographic characteristics overlapping those of rheumatoid arthritis and osteoarthritis. For unknown reasons, chronic pyrophosphate arthropathy has a predilection for knees, wrists, shoulders, elbows, hips, ankles, midtarsal joints, and small joints of the hands—many of which are atypical sites for primary osteoarthritis. More rarely, chronic pyrophosphate arthropathy can be associated with hemorrhagic arthritis. Although the vast majority of CPPD deposition disease is idiopathic, approximately 20% of cases are associated with

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underlying metabolic disorders such as hyperparathyroidism, hypomagnesemia, hypophosphatasia, and hemochromatosis. These associations undoubtedly stem from the roles of calcium, magnesium, alkaline phosphatase, and iron in chondrocyte-mediated pathways of ATP metabolism (magnesium, alkaline phosphatase) as well as crystal formation (calcium, iron). Of note, secondary forms of CPPD deposition disease may be the presenting clinical finding of the associated systemic disorder, typically occurring at an earlier age than idiopathic cases and often involving specific joints such as the second and third metacarpophalangeal joints.

DIAGNOSIS AND TREATMENT Detection of chondrocalcinosis on radiographs suggests, but does not establish, the diagnosis of CPPD arthropathy. Synovial fluid aspiration with demonstration of intracellular, positively birefringent, rhomboid-shaped crystals is therefore necessary to confirm the diagnosis of pseudogout or chronic pyrophosphate arthropathy (see Fig. 87-3). However, crystals may be small, fragmented, and difficult to detect, partly reflecting their susceptibility to degradation. Acute attacks of CPPD arthropathy are effectively treated with NSAIDs or with intra-articular glucocorticoids, although joint aspiration alone can be therapeutic. Low-dose colchicine may be effective in preventing recurrent attacks of pseudogout or managing persistent inflammation in chronic pyrophosphate arthropathy.

Other Crystal Disorders Hydroxyapatite crystals are composed of basic calcium phosphates and deposit at soft tissue sites, particularly tendons and bursae. Although hydroxyapatite deposition in peri-articular structures such as the supraspinatus tendon and subacromial bursa can result in calcific tendinitis, shedding of crystals into the actual joint space can produce exuberant synovitis and a destructive arthropathy (including the “Milwaukee shoulder” syndrome). Oxalate crystals, on the other hand, may deposit in cartilage and intervertebral discs.

Prospectus for the Future Future studies of long-term use will help define the role of new agents such as pegylated uricase and febuxostat in the prevention and management of gout.

References Becker MA, Schumacher HR, Wortmann RL, et al: Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 353:24502461, 2005. Doherty M: Calcium pyrophosphate dihydrate crystal-associated arthropathy. In Hochberg M, Silman A, Smolen J, et al (eds): Rheumatology, 3rd ed. Philadelphia, Mosby, 2003, pp 1937-1950. Hershfield MS: Gout and uric acid metabolism. In Goldman L, Bennett JC (eds): Cecil Textbook of Medicine, 21st ed. Philadelphia, WB Saunders, 2000, pp 1541-1548. Kanellis J, Feig DI, Johnson RJ: Does asymptomatic hyperuricemia contribute to the development of renal and cardiovascular disease? An old controversy renewed. Nephrology 9:394-399, 2004.

Kelley WN, Wortmann RL: Gout and hyperuricemia. In Kelley WN, Harris ED Jr, Ruddy S, Sledge CB (eds): Textbook of Rheumatology, 5th ed. Philadelphia, WB Saunders, 1997, p 1313. McLean L: The pathogenesis of gout. In Hochberg, M, Silman A, Smolen J, et al (eds): Rheumatology, 3rd ed. Philadelphia, Mosby, 2003, pp 1903-1918. Ryan LM, McCarty DJ: Calcium pyrophosphate crystal deposition disease, pseudogout and articular chondrocalcinosis. In Koopman WJ (ed): Arthritis and Allied Conditions, 13th ed. Baltimore, Williams & Wilkins, 1997, p 2103. Schumacher HR Jr: Crystal deposition arthropathies. In Goldman L, Bennett JC (eds): Cecil Textbook of Medicine, 21st ed. Philadelphia, WB Saunders, 2000, pp 1548-1550. Stamp LK, O’Donnell, JL, Chapman PT: Emerging therapies in the long-term management of hyperuricemia and gout. Intern Med J 37:258-266, 2007.

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Osteoarthritis ss

C. Kent Kwoh

Epidemiology Osteoarthritis (OA), also known as degenerative joint disease (DJD), is the most common arthritis and musculoskeletal disease. Over 26.9 million Americans over the age of 25 have some form of OA, and the prevalence of OA increases with age. The prevalence of radiographic OA varies by the joint involved, with 27.2% of all adults and over 80% of those over 65 having evidence of hand OA. With regard to knee OA, 37.4% of those over age 60 have radiographic evidence of disease. The prevalence of symptomatic OA is lower, with 6.8% of all adults having evidence of symptomatic hand OA and 16.7% of those over age 45 having evidence of symptomatic knee involvement. Hand and knee OA is more common among women, especially after age 50, and also is more common among African Americans. Nodal OA, involving the distal and proximal interphalangeal joints, is significantly more common in women and also is more common among female first-degree relatives. OA is associated with major morbidity and is the leading cause of long-term disability in the United States. Lower extremity OA is the most common cause of difficulty with walking or climbing stairs, preventing an estimated 100,000 elderly Americans from independently walking from bed to bathroom. OA has a large economic impact as the result of both direct medical costs (e.g., physician visits, laboratory tests, medications, surgical procedures) and indirect costs (e.g., lost wages, home care, lost wage-earning opportunities). With the aging of the U.S. population, the burden of OA is expected to increase throughout the coming years.

Pathologic Factors The causes of OA are complex and heterogeneous, and there is limited understanding of its pathophysiology. Its cardinal feature is progressive loss of articular cartilage with associated remodeling of subchondral bone. OA is best defined as joint failure, a disease process that involves the total joint including the subchondral bone, ligaments, joint capsule, synovial membrane, periarticular muscles, and articular car870

tilage. Joint failure may result from a variety of pathways subsequent to bone trauma and repetitive injury: joint instability caused by muscle weakness and ligamentous laxity; nerve injury and neuronal sensitization and/or hyperexcitability; low-grade systemic inflammation caused by subacute metabolic syndrome; or local inflammation resulting from synovitis. OA is a complex disorder with one or more identifiable risk factors, which range from biomechanical, metabolic, or inflammatory processes, to congenital or developmental deformities of the joint, to genetic factors. As noted previously, age, sex, and race are prominent risk factors for OA. Biomechanical contributors include repetitive or isolated joint trauma related to certain occupations or physical activities that involve repeated joint stress and thus predispose an individual to early OA. Obesity may contribute from a biomechanical perspective or a systemic perspective related to a subacute metabolic syndrome. Certain metabolic disorders such as hemochromatosis and ochronosis are also associated with OA. High bone mineral density (BMD) has been shown to be associated with hip or knee OA. Estrogen deficiency may be a risk factor for hip or knee OA. Candidate gene studies and genome wide scans have identified a number of potential genetic markers of OA. Inflammatory joint diseases such as rheumatoid arthritis may result in cartilage degradation and biomechanical factors that lead to secondary OA. The destruction of the joint, including wearing away of articular cartilage, is therefore best viewed as the final product of a variety of possible etiologic factors. The earliest finding in OA is fibrillation of the most superficial layer of the articular cartilage. With time, the disruption of the articular surface becomes deeper, with extension of the fibrillations to subchondral bone, fragmentation of cartilage with release into the joint, matrix degradation, and, eventually, complete loss of cartilage, leaving only exposed bone. Early in this process the cartilage matrix undergoes significant change, with increased water and decreased proteoglycan content. This progression is in contrast to the dehydration of cartilage that occurs with aging. The tidemark zone, separating the calcified cartilage from the radial zone, becomes invaded with capillaries. Chondrocytes initially are

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metabolically active and release a variety of cytokines and metalloproteinases, contributing to matrix degradation, which in the later stages results in the penetration of fissures to the subchondral bone and the release of fibrillated cartilage into the joint space. An imbalance between tissue inhibitors of metalloproteinases and the production of metalloproteinases may be operative in OA. Subchondral bone increases in density and cystlike bone cavities containing myxoid, fibrous, or cartilaginous tissue occur. Osteophytes, or bony proliferations at the margin of joints at the site of bone-cartilage interface, may also form at capsule insertions. Osteophytes contribute to joint-motion restriction and are thought to be the result of new bone formation in response to the degeneration of articular cartilage, but the precise mechanism for their production remains unknown. A variety of crystals has been identified in synovial fluid and other tissues from osteoarthritic joints, most notably calcium pyrophosphate dihydrate and apatite. Although these crystals clearly have potent inflammatory potential, their role in the pathogenesis of OA remains unclear. Frequently these crystals are asymptomatic and do not correlate with extent or severity of disease. The diversity of risk factors predisposing to OA suggests that a wide variety of insults to the joints, including biomechanical trauma, chronic articular inflammation, and genetic and metabolic factors, can contribute to or trigger the cascade of events that results in the characteristic pathologic features of OA described earlier. At some point, the cartilage degradative process becomes irreversible, perhaps the result of an imbalance of regulatory molecules such as tissue inhibitors of metalloproteinases. With progressive changes in articular cartilage, joint mechanics become altered, in turn perpetuating the degradative process.

been identified. The nodal form of OA, involving primarily the distal interphalangeal joints, is most common in middleaged women, typically with a strong family history among first-degree relatives. Erosive, inflammatory OA is associated with prominent erosive, destructive changes, especially in the finger joints, and may suggest rheumatoid arthritis, although systemic inflammatory signs and other typical features of rheumatoid arthritis (e.g., nodules, proliferative synovitis, extra-articular features, rheumatoid factor) are absent. The diagnosis of OA is based on history, physical examination, and characteristic radiographic features. The physician must distinguish OA from other inflammatory joint diseases such as rheumatoid arthritis. Distinguishing OA from inflammatory joint diseases involves identifying the characteristic pattern of joint involvement and the nature of the individual joint deformity. Joints commonly involved in OA include the distal interphalangeal joints, proximal interphalangeal joints, first carpometacarpal joints, facet joints of the cervical and lumbar spine, hips, knees, and first metatarsophalangeal joints. Heberden and Bouchard nodes may be present in the hands. Involvement of the wrist, elbows, shoulders, and ankles is uncommon, except in the case of trauma, congenital disease, or endocrine or metabolic disease. The characteristic radiographic features of OA include subchondral sclerosis, joint-space narrowing, subchondral cysts, and osteophytes. The advent of magnetic resonance imaging (MRI) has demonstrated that additional morphologic abnormalities such as bone marrow lesions and meniscal degeneration may also be important features of OA.

Clinical Features and Diagnosis

The natural history of OA is quite variable, with periods of relative stability interspersed with rapid deterioration. The management of OA should therefore be tailored to the individual patient and may include a combination of nonpharmacologic, pharmacologic, and surgical approaches. Patients should be educated regarding the objectives of treatment and the importance of changes in lifestyle, exercise, pacing of activities, and other measures to unload the damaged joint(s). The initial focus should be on self-help and patientdriven treatments rather than on passive therapies. Emphasis should be placed on encouraging adherence to both nonpharmacologic and pharmacologic therapies. Physical therapists may be helpful in providing instruction in appropriate exercises to reduce pain and preserve functional capacity. For knee and hip OA, assistive devices such as walking aids may be useful. Regular aerobic, musclestrengthening and range-of-motion exercises may also be beneficial. Overweight patients with knee or hip OA should be encouraged to lose weight. A knee brace can reduce pain, improve stability, and diminish the risk of falling for patients with knee OA and mild or moderate varus or valgus instability. Advice concerning appropriate footwear is also important. For example, lateral wedged insoles can be of symptomatic benefit for some patients with medial tibiofemoral compartment OA. Spinal orthoses may provide benefit to patients with significant cervical or lumbar OA. Local applications of heat, ultrasound, or transcutaneous

Pain is the characteristic clinical feature of OA. Recent research has found that pain in OA may be reported as either a constant aching or as a more severe, intermittent pain. Pain is generally worse with activity and/or weight bearing and better with rest. In later stages pain may also occur at rest. Pain tends to be localized to the specific joint involved but may also be referred to a more distant site. The cause of the pain is unclear and is likely to be heterogeneous. Pain may be the result of an interaction among structural pathology; the motor, sensory, and autonomic innervation of the joint; and pain processing at both the spinal and cortical levels, as well as specific individual and environmental factors. Stiffness may be present, particularly after prolonged inactivity, but is not a major feature and is of short duration, usually lasting for passive 0

Active = passive +/0

Table 89-2 Bursitis Syndromes Location

Symptom

Finding

Subacromial Olecranon Iliopectineal Trochanteric

Shoulder pain Elbow pain Groin pain Lateral hip pain Anterior knee pain Anterior knee pain

Tender subacromial space Tender olecranon swelling Tender inguinal region Tender at greater trochanter Tender swelling over patella Tender swelling lateral or medial to patellar tendon Tender medioproximal tibia (below joint line of knee) Tender ischial spine (at gluteal fold) Tender swelling between Achilles tendon insertion and calcaneus Tender central heel pad

Prepatellar Infrapatellar

0 +

+ 0

Anserine

Medial knee pain

0 +/0

+ 0

Ischiogluteal

Buttock pain

Retrocalcaneal

Heel pain

Calcaneal

Heel pain

Swelling Synovial (fusiform) Local +, present; 0, absent.

Diagnosis of Nonarticular Soft Tissue Disorders Tendinitis, bursitis, and myofascial disorders should be distinguished from articular disorders. In most cases, this can be accomplished by a careful examination of the involved structure (Table 89-1). General principles of the musculo skeletal examination are as follows: 1. Observation: If deformity or soft tissue swelling is present, then is it fusiform (surrounding the entire joint in a symmetrical fashion) or is it localized? Local rather than fusiform deformity distinguishes nonarticular disorders from articular disorders. 2. Palpation: Is tenderness localized or in a fusiform distribution? Is an effusion present? Local, not fusiform or joint-line, tenderness distinguishes nonarticular disorders from articular disorders. The presence of an effusion almost always indicates an articular disorder. 3. Assessing range of motion: The musculoskeletal examination includes the assessment of both active range of motion (i.e., the patient attempts to move the sympto matic structure) and passive range of motion (i.e., the examiner moves the symptomatic structure). Articular disorders are generally characterized by equal impairment in both active and passive movements as a result of the mechanical limitation of joint motion resulting from proliferation of the synovial membrane, the presence of an effusion, or the derangement of intra-articular structures. Impairment of active movement characterizes nonarticular disorders to a much greater degree than passive movement.

Bursitis CLINICAL PRESENTATION Septic Bursitis Superficial forms of bursitis, particularly olecranon bursitis and prepatellar and occasionally infrapatellar bursitis, are more frequently infected or involved with crystal deposition

than are deep forms of bursitis. Presumably, these infections or involvements are the result of direct extension of organisms through subcutaneous tissues. Most commonly, Staphylococcus aureus is isolated from infected superficial bursae. Septic bursitis should be suspected where there is cellulitis, erythema, fever, and peripheral leukocytosis. Definitive diagnosis and especially exclusion of infection of subcutaneous bursae generally require aspiration of the distended bursa. The bursal fluid should be assessed for cell count, Gram stain, and culture and examined for crystals.

Nonseptic Bursitis Nonseptic bursitis frequently appears as an overuse condition associated with sudden or unaccustomed repetitive activity of the associated extremity. The two most common types of bursitis are subacromial and trochanteric bursitis (Table 89-2). Subacromial bursitis is the most common overall cause of shoulder pain over the lateral upper arm or deltoid muscle that is exacerbated with abduction of the arm. Subacromial bursitis is the result of compression of the inflamed rotator cuff tendon between the acromion and humeral head. Because the rotator cuff forms the floor of the subacromial bursa, bursitis in this location often results from tendinitis of the rotator cuff. Occasionally, subacromial bursitis or rotator cuff tendinitis results from osteophyte compression of the rotator cuff tendon originating from the acromioclavicular joint. The differential diagnosis includes tears of the rotator cuff, intra-articular pathologic mechanisms of the glenohumeral joint, bicipital tendinitis, cervical radiculopathy, and referred pain from the chest. Trochanteric bursitis is the result of inflammation at the insertion of the gluteal muscles at the greater trochanter and produces lateral thigh pain, which is often worse when the subject lies on the affected side. Women seem to be more prone to develop this condition, perhaps because of increased traction of the gluteal muscles as a result of the relatively broader female pelvis. Other potential risk factors include weight gain, local trauma, overuse activities such as jogging, and leg-length discrepancies (primarily on the side with the

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Table 89-3 Tendinitis Syndromes Location

Symptom

Finding

Extensor pollicis brevis and abductor pollicis longus (de Quervain tenosynovitis) Flexor tendons of fingers

Wrist pain

Pain on ulnar deviation of the wrist, with the thumb grasped by the remaining four fingers (Finkelstein test) Tender nodule on flexor tendon on palm over metacarpal joint Tenderness of medial epicondyle Tenderness of lateral epicondyle Tenderness along bicipital groove Tenderness at insertion of patellar tendon Tender Achilles tendon Tenderness under medial malleolus with resisted inversion of the ankle Tenderness under lateral malleolus with passive inversion

Medial epicondyle Lateral epicondyle Bicipital tendon Patella Achilles Tibialis posterior

Triggering or locking of fingers in flexion Elbow pain Elbow pain Shoulder pain Knee pain Heel pain Medial ankle pain

Peroneal

Lateral midfoot or ankle pain

longer leg). These factors are thought to lead to increased tension of the gluteus maximus on the iliotibial band, producing bursal inflammation. The differential diagnosis of trochanteric bursitis includes lumbar radiculopathy (particularly of the L1 and L2 nerve roots), meralgia paresthetica (entrapment of the lateral cutaneous nerve of the thigh as it passes under the inguinal ligament), true hip joint disease, and intra-abdominal pathologic processes. Other bursitis syndromes are less common and listed in Table 89-2.

TREATMENT Septic bursitis is treated with a combination of serial aspirations of the infected bursa and antibiotics, initially directed against S. aureus and then adjusted depending on the results of bursal fluid cultures. Recurrent septic bursitis may need surgical excision of the bursa in recalcitrant cases. The approach to nonseptic bursitis should include rest, local heat, and, unless contraindicated (e.g., by peptic ulcer disease, renal disease, advanced age), non steroidal anti-inflammatory drugs (NSAIDs). Usually, the most effective approach is a local injection of a corticosteroid. Superficial bursae with obvious swelling should be aspirated before the corticosteroid is injected. For deep bursae, such as the subacromial or trochanteric bursae, aspiration yields little if any fluid, and direct injection of a corticosteroid without attempted aspiration is reasonable. Caution is advised in attempted aspiration or injection of the iliopsoas bursa, the ischiogluteal bursa, and the gastrocnemius-semimembranosus bursa (Baker cyst). These bursae lie close to important neural and/or vascular structures, and aspiration under radiologic (ultrasound) guidance may be a safer option.

Tendinitis CLINICAL PRESENTATION Most tendinitis syndromes are the result of inflammation in the tendon sheath. Overuse with microscopic tearing of the tendon is the most common risk factor for tendinitis, but tendon compression by an osteophyte may occur, for

example, in the rotator cuff tendon compressed by an osteophyte originating from the acromioclavicular joint. One of the most common forms of tendinitis is lateral epicondylitis, also known as tennis elbow (Table 89-3). This is a common overuse syndrome among tennis players, but it can be seen in many other settings requiring repetitive extension of the forearm (e.g., painting overhead). The diagnosis is confirmed by exclusion of elbow joint pathology and the finding of local tenderness at the lateral epicondyle, which is typically exacerbated by forearm extension against resistance. Enthesopathies such as Achilles tendinitis and peroneal and posterior tibial tendinitis may occur in the setting of an underlying seronegative arthropathy such as Reiter disease or psoriatic arthritis. A history and clinical evaluation for these disorders should be pursued in the appropriate patient.

TREATMENT Therapy for tendinitis—NSAIDs, local heat, and corticosteroid injection—is similar to that for bursitis. Rest, physical therapy, occupational therapy, and occasionally ergonomic modification are useful adjuncts. The goal of corticosteroid injection in tendinitis is to infiltrate the tendon sheath rather than the tendon itself, because direct injection into a tendon may result in rupture of the tendon. Corticosteroid injection of the Achilles tendon should be avoided because of the propensity of this tendon to rupture. Surgical management of tendinitis is indicated only with failures of conservative treatment. For example, chronic impingement of the supraspinatus tendon that is refractory to conservative treatment may require subacromial decompression.

Fibromyalgia Syndrome Fibromyalgia syndrome, formerly known as fibrositis, is a controversial chronic pain condition characterized by persistent, widespread pain and tenderness to palpation at anatomically defined tender points located in soft tissue musculoskeletal structures. Associated systemic symptoms can include insomnia, cognitive dysfunction, depression, anxiety, recurrent headaches, dizziness, fatigue, morning

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stiffness, extremity dysesthesia, irritable bowel syndrome, and irritable bladder syndrome. Although the syndrome has only recently been the subject of investigation, descriptions of it exist far back in the medical literature. Controversy persists, however, because of the lack of objective diagnostic or pathologic findings.

PATHOPHYSIOLOGIC FEATURES ss

Fibromyalgia syndrome as defined by the American College of Rheumatology 1990 definition for clinical trials is a chronic widespread pain condition with characteristic tender points on physical examination, often associated with a constellation of symptoms such as fatigue, sleep disturbance, headache, irritable bowel syndrome, and mood disorders. Investigators have examined diverse mechanisms in fibromyalgia syndrome, including studies of muscle, sleep physiologic processes, neurohormonal function, and psychological status. Although the pathophysiologic mechanisms remain unknown, an increasing body of literature points to central (central nervous system) rather than peripheral (muscle) mechanisms. Muscle tissue has been a focus of investigation for many years. Initial studies, including histologic and histochemical studies, suggested a possible metabolic myopathy; however, carefully controlled studies indicated that these abnormalities were simply the result of deconditioning. Sleep studies suggested that disruption of deep sleep (stage IV) by so-called alpha-intrusion (the normal awake electroencephalographic pattern) may play a causal role, but this finding was later observed in other disorders, more likely indicating effect rather than cause. In some cases, musculoskeletal injury has been implicated as a trigger for fibromyalgia, but social and legal issues cloud its causative role. Several studies have suggested that subtle hypothalamicpituitary-adrenal axis hypofunction may occur in fibromyalgia syndrome, although it remains uncertain whether these changes are constitutive or are the result of fibromyalgia. A prevailing theory of pathogenesis is dysregulation of pain pathways leading to central sensitization and marked by neurotransmitter, neurohormone, and sleep physiology irregularities. Fibromyalgia has long been linked to psychological disturbance. Most studies have confirmed high lifetime rates of major depression, which range from 34% to 71%, associated with fibromyalgia syndrome. High lifetime rates of migraine, irritable bowel syndrome, and panic disorder have also been associated with fibromyalgia syndrome, suggesting that fibromyalgia may be part of an affective spectrum group of disorders.

CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS The clinical presentation of fibromyalgia syndrome is generally that of the insidious onset of chronic, diffuse, poorly localized musculoskeletal pain, typically accompanied by fatigue and sleep disturbance. The physical examination shows a normal musculoskeletal examination, with no deformity or synovitis; however, widespread tenderness occurs, especially at tendon insertion sites, indicating a general reduction in pain threshold. The American College of Rheumatology has published the results of a multicenter

Table 89-4 American College of Rheumatology Classification Criteria for Fibromyalgia Syndrome For classification purposes, patients are said to have fibromyalgia if both criteria are satisfied. 1. History of chronic, widespread pain: Pain is considered widespread when present above and below the waist on both sides of the body. Chronic is defined as greater than 3 months in duration. 2. Pain in 11 of 18 tender points on digital palpation: Points include occiput, low cervical, trapezius, supraspinatus, second rib, lateral epicondyle, gluteal, greater trochanter, knee.

study to identify clinical classification criteria for fibromyalgia syndrome, which were shown to have high sensitivity and specificity (Table 89-4). These criteria have facilitated population-based studies, which suggest that fibromyalgia syndrome affects approximately 2% of the population and up to 7% of women. Approximately 10% of surveyed patients are disabled to varying degrees by their symptoms; therefore the economic impact is large. The prevalence of fibromyalgia appears to be similar in most ethnic and racial groups. Approximately one third of the patients identify antecedent trauma as a precipitant for their symptoms, one third of patients describe a viral prodrome, and one third have no clear precipitant. A variety of less typical presentations has been described, including a predominantly neuropathic presentation with paresthesias (numbness and tingling) in a nondermatomal distribution, an arthralgic rather than myalgic presentation, and an axial skeletal presentation (resembling degenerative disk disease). Many patients may have undergone invasive diagnostic tests and in some cases inappropriate procedures such as carpal tunnel release or cervical or lumbar laminectomies. Conditions that should be considered in the differential diagnosis of fibromyalgia syndrome include polymyalgia rheumatica (in older patients), hypothyroidism, polymyositis, and early systemic lupus erythematosus or rheumatoid arthritis. In general, however, symptoms are exhibited for many months or years without evidence of other signs or symptoms of an underlying connective tissue disease, making other possible diagnoses unlikely. Laboratory and radiographic studies are usually normal in patients with fibromyalgia syndrome. Exclusion of other conditions, such as osteoarthritis, rheumatoid arthritis, and systemic lupus erythematosus, by radiography, erythrocyte sedimentation rate, assays for rheumatoid factor or antinuclear antibody, and other tests is no longer considered a necessary preliminary to the diagnosis of fibromyalgia syndrome, which should be diagnosed on the basis of positive criteria.

TREATMENT The treatment of fibromyalgia includes reassurance that the condition is not a progressive, crippling, or life-threatening entity. A combination of treatment options, including medication and physical measures, is helpful in most patients. Medications shown to be helpful in short-term, double-blind, placebo-controlled trials include amitriptyline

Chapter 89—Nonarticular Soft Tissue Disorders and cyclobenzaprine. Low doses of these medications (e.g., 10 to 30 mg of amitriptyline, 10 to 30 mg of cyclobenza prine) are moderately effective and generally well tolerated. Studies have also shown that newer antidepressants of the serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine, bupropion) and α2δ ligands (gabapentin, pregabalin) are also effective, particularly in combination with low doses of tricyclic antidepressants. Patients should

Prospectus for the Future Better understanding of pathophysiology and improved trial design and outcome measures will facilitate the development of more effective therapies in soft tissue disorders.

References Goldenberg DL, Burkhardt C, Crofford L: Management of fibromyalgia syndrome. JAMA 292:2388-2395, 2004. Littlejohn GO: Balanced treatments for fibromyalgia. Arthritis Rheum 50:2725-2729, 2004.

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also be encouraged to take an active role in the management of their condition. They should, if possible, begin a progressive, low-level aerobic exercise program to improve muscular fitness and a sense of well-being. A combination approach is effective in most patients in alleviating symptoms, although a small minority of patients require more intensive treatment strategies, such as psychiatric treatment or referral to a pain center.

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ss

Chapter

90

Rheumatic Manifestations of Systemic Disorders Fotios Koumpouras

M

any systemic disorders can express themselves through the musculoskeletal system. These often can be the presenting clue for the true nature of the underlying disorder (Table 90-1).

osteal new bone formation, especially along the distal and/ or proximal portion of long bones. Treatment of the underlying disorder ameliorates HOA.

LEUKEMIA AND LYMPHOMA

Rheumatic Syndromes Associated with Malignancy HYPERTROPHIC OSTEOARTHROPATHY Hypertrophic osteoarthropathy (HOA) is a syndrome that includes clubbing of fingers and toes, periostitis of the long bones, and arthritis. HOA can be primary, which is a hereditary form appearing in childhood and usually self-limited, or secondary. The secondary form can be either generalized or localized. Secondary generalized HOA is most often associated with neoplastic disease or infectious disease but can be seen in congenital heart disease, inflammatory bowel disease, cirrhosis, or Graves disease. Approximately 90% of cases are associated with lung cancer. Secondary localized HOA has been associated with hemiplegia, aneurysms, infective arteritis, and patent ductus arteriosus. In addition, isolated digital clubbing is associated with pleuropulmonary disease in approximately 80% of patients, but cancer is present in only a small minority of patients. Chronic digital clubbing does not appear to lead to the development of HOA. The long bones most commonly involved in HOA are the distal femur, tibia, and radius. The pathogenesis is unknown, although platelet-endothelial interactions with production of von Willebrand factor are thought to be important mechanisms. HOA typically produces bone and joint pain with swelling that results from peri-articular periostitis. Joints appear swollen, but no proliferative synovium or inflammation develops, and joint fluid is noninflammatory. Radiographic features can be diagnostic and include periostitis with peri878

Leukemia may simulate various rheumatic syndromes by producing synovitis or bone pain resulting from direct invasion of the synovium or marrow expansion. Approximately 6% of adult patients with leukemia exhibit rheumatic manifestations, which precede the diagnosis of leukemia by an average of 3 months. The most common presentation is an asymmetric large-joint oligoarthritis, often accompanied by low back pain. Up to 60% of children with acute leukemia have been diagnosed with either monoarthritis or polyarthritis. Although lymphoma is frequently associated with bone lesions, arthritis is a rare presentation. The combination of nocturnal bone pain, hematologic abnormalities, and radiographic features such as periosteal elevation should suggest the possibility of leukemia. Treatment of the leukemia usually results in resolution of the musculoskeletal manifestations. Vasculitis may also occur with leukemia, lymphoma, and other myelodysplastic disorders. Leukocytoclastic vasculitis is the most common clinical vasculitic paraneoplastic presentation. In addition, a polyarteritis nodosa–like vasculitis is the most common rheumatologic manifestation of hairy cell leukemia. The presentation of vasculitis may proceed or follow the malignancy diagnosis. The most common malignancies associated with vasculitis include hairy cell leukemia, leukemia, multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, sarcoma, cervical carcinoma, breast carcinoma, prostate carcinoma, and colon cancer. Sweet syndrome is an acute febrile neutrophilic dermatosis that mimics vasculitis and is associated with malignancy in approximately 15% of patients. It is most commonly seen with acute myelogenous leukemia but has been described with other types of malignancies. It can be associated with an acute, self-limited polyarthritis in 20% of the cases.

Chapter 90—Rheumatic Manifestations of Systemic Disorders Table 90-1 Systemic Conditions Associated with Rheumatic Manifestations Malignant Disorders Hypertrophic osteoarthropathy Lymphoma Leukemia Carcinoma polyarthritis Hematologic Disorders Hemophilia Sickle cell disease Thalassemia Multiple myeloma Amyloidosis Gastrointestinal Disorders Spondyloarthropathies Whipple disease Hemochromatosis Primary biliary cirrhosis Endocrinopathies Diabetes Hypothyroidism Hyperthyroidism Hyperparathyroidism Acromegaly

Hematologic Disorders HEMOPHILIA Hemarthrosis is the most common bleeding complication of either hemophilia A (factor VIII deficiency) or hemophilia B (factor IX deficiency) and occurs in up to two thirds of patients. Hemarthrosis may occur spontaneously or as the result of minor trauma, and the level of factor deficiency determines its frequency and age at onset. Acute, painful swelling of the knees, elbows, and ankles is the most common presentation. A chronic arthropathy with persistent synovitis may also occur, perhaps as a result of excessive iron deposition in synovial membrane and cartilage. Radiographic findings are those of degenerative joint disease, with joint space narrowing, subchondral sclerosis, and cyst formation. Widening of the femoral condylar notch is a late, diagnostic radiographic finding. Treatment consists of prompt administration of factor VIII or IX concentrate or recombinant forms, intra-articular corticosteroid injections, local ice application, rest, and later physical therapy. Aspiration is indicated only if concomitant sepsis is suggested or if the joint is unusually tense and only after factor replacement. No evidence suggests that prophylaxis for acute hemarthrosis may reduce the incidence of chronic synovitis and future joint damage.

SICKLE CELL DISEASE Of the sickle cell hemoglobinopathies, sickle cell (SS) anemia, sickle cell–β-thalassemia, sickle cell–hemoglobin C (SC) disease, and sickle cell–hemoglobin D (SD) disease all produce musculoskeletal complications, which include painful crises, arthropathy, dactylitis, osteonecrosis, osteomyelitis, and gout. SS crises are the most common musculoskeletal features, producing pain in the chest, back, and joints. Involvement of joints may produce a painful arthritis,

879

typically of the large joints. The mechanism of the arthropathy is thought to be an articular reaction to juxta-articular bone infarction or infarction of the synovial membrane by vascular occlusion from sickled erythrocytes. The synovial fluid is typically noninflammatory. Dactylitis resulting from vaso-occlusion in bone may occur in infants and young children, producing acute, painful, nonpitting edema of the hands and feet (hand-foot syndrome). This usually resolves spontaneously in a few weeks. Osteonecrosis of the femoral head, shoulder, and tibial plateau (in decreasing frequency) may also result from repeated crises and is most common in SS disease. An increased incidence of septic arthritis and osteomyelitis has been associated with SS disease; Salmonella is the bacterial genus most frequently isolated in the patient with osteomyelitis (approximately 50%). Predisposition to Salmonella species is thought to be caused by functional asplenia. Osteomyelitis may be subtle and is often confused with sickle crisis. Bandemia is more suggestive of osteomyelitis. Combined technetium and gallium nuclear scans can be employed to help diagnosis. In addition, hyperuricemia caused by renal tubular damage secondary to sickle cell disease can be seen in up to 40% of adult patients. Therefore gout can occur in patients with sickle cell disease, although it is uncommon. In children with sickle cell disease, hyperuricosuria without hyperuricemia occurs, presumably resulting from the increased marrow turnover and urate production. Noninflammatory joint effusions adjacent to areas of bony crisis can occur, particularly at the knees and ankles. Focal muscle necroses as well as rhabdomyolysis are uncommon to rare manifestations.

MULTIPLE MYELOMA AND AMYLOIDOSIS Multiple myeloma is one of the most common plasma cell dyscrasias and is frequently accompanied by musculoskeletal manifestations, which include bone pain resulting from lytic bone lesions, pathologic fractures, and osteoporosis. The diagnosis of multiple myeloma should be suggested in any of these clinical settings and is confirmed with the finding of a monoclonal gammopathy and sheets of immature neoplastic plasma cells on bone marrow biopsy. Primary (AL) amyloidosis accompanies approximately 15% of patients with myeloma. Alternatively, AL amyloidosis occurs without significant plasma cell proliferation on bone marrow biopsy, but patients have evidence of a plasma cell dyscrasia by virtue of the presence of a serum monoclonal gammopathy. AL amyloidosis results when amyloid protein, consisting of microscopic fibrils derived from monoclonal light chains, is deposited in organs such as the kidneys, heart, peripheral nerves, and gastrointestinal tract. It should be considered in the differential diagnosis of a patient older than 40 years of age who has nephritic syndrome, unexplained heart failure, idiopathic peripheral neuropathy, or hepatomegaly. Infrequently, amyloid joint infiltration produces a symmetrical, small-joint polyarthritis-simulating rheumatoid arthritis. Occasionally, significant infiltration of the shoulder joints with amyloid deposits produces an anterior glenohumeral soft tissue deformity known as the shoulder pad sign. Macroglossia and submandibular gland infiltration may also

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occur. The diagnosis of this form of amyloidosis is the most easily established, with the demonstration of apple-green birefringent fluorescence on Congo red staining of an abdominal fat pad aspirate, or rectal mucosal biopsy. Biopsy of affected areas, such as gastric mucosa in those with stomach involvement, also has a high yield. In addition, immunoelectrophoresis and immunofixation of serum and urine should be performed. Optimal treatment of AL amyloidosis now consists of high-dose chemotherapy with stem cell transplantation. The three other principal systemic forms of amyloidosis are (1) secondary (AA) amyloidosis, (2) heredofamilial (familial amyloid polyneuropathy) amyloidosis, and (3) β2microglobulin–associated (β2M) amyloidosis. AA amyloidosis is a rare complication of chronic inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease, and familial Mediterranean fever. Certain chronic infections such as leprosy, tuberculosis, and osteomyelitis are also associated with this form of amyloidosis. The amyloid fibrils are derived from the acute phase reactant, serum amyloid A protein. The disease usually causes proteinuria or gastrointestinal symptoms because of infiltration of the kidney or gastrointestinal tract. The diagnosis generally requires organ biopsy because the sensitivity of the abdominal fat pad aspirate is considerably lower in AA amyloidosis than it is in the AL form. Treatment consists of controlling the underlying disorder, producing the chronic inflammatory process. Heredofamilial (familial amyloid polyneuropathy) amyloidosis is the least common form of amyloidosis. This rare autosomal dominant disease is the result of single-point mutations in the gene coding for transthyretin, a thyroidtransport protein. Transthyretin is synthesized principally in the liver. Amyloid fibrils in this disease are composed of fragments of mutant transthyretin that have a propensity to form amyloid fibrils. The condition typically causes an axonal and/or autonomic neuropathy late in life. Abdominal fat aspiration has high sensitivity in the diagnosis of this type of amyloidosis. Studies suggest that the optimal treatment is orthotopic liver transplantation, which prevents further production of the mutant transthyretin. β2M-associated amyloidosis occurs almost exclusively in patients on long-standing hemodialysis. This disease typically causes carpal tunnel syndrome and flexor tendon deposits in the hands or in the rotator cuff. Cystic bone deposits in the carpal bones, hips, shoulders, and cervical spine have also been described. The pathogenesis of β2Massociated amyloidosis is not completely understood but may in part be the result of altered proteolysis of β2microglobulin in long-standing hemodialysis. Treatment includes physical measures such as splinting for carpal tunnel syndrome and physical therapy for shoulder involvement. Anti-inflammatory agents may provide additional symptomatic relief. Surgical removal of carpal or shoulder deposits may be required. Renal transplantation may be the most effective way to halt progression.

Gastrointestinal Diseases WHIPPLE DISEASE Whipple disease is a rare, multisystemic disease of late middle-aged to older men and is characterized by the

presence of fever, abdominal pain, steatorrhea with weight loss, lymphadenopathy, and arthritis, the last of which is now known to be the result of infection with Tropheryma whippleii. Polyserositis, arterial hypotension, hyperpigmentation, and various central nervous system manifestations, such as personality changes, memory loss, dementia, and spastic paraparesis, may also occur. The organism’s DNA can be detected in duodenal biopsy specimens. Biopsy has long been used to detect this unculturable organism in histiocytes of the lamina propria, which show intracytoplasmic inclusions of irregular granular material that is positive on periodic acid-Schiff staining. This last finding is not specific for Whipple disease, and therefore polymerase chain reaction assay to detect the organism’s DNA is now the preferred technique for diagnosis. The arthritis of Whipple disease occurs in 60% to 90% of patients and is the most common prodrome. Classically, the arthritis is an intermittent migratory oligoarthritis lasting from a few hours to days with spontaneous remission. Some patients have only arthralgia, whereas others have a florid polyarthritis. Synovial fluid findings are typically inflammatory with a high percentage of mononuclear cells. Treatment consists of antibiotic therapy with tetracycline, which results in complete resolution within 1 week to 1 month.

HEMOCHROMATOSIS Hereditary hemochromatosis is an autosomal recessive disorder associated with increased iron absorption and deposition that, via hemosiderin, eventually produces multiorgan damage. Hemochromatosis is among the most common genetic diseases among Europeans, with a homozygous prevalence of 0.3% to 0.5% and a heterozygote frequency of 6.7% to 10%. Approximately 90% of white patients with hereditary hemochromatosis are homozygous for the same mutation (C282Y) in the HFE gene. HFE protein forms complexes with the transferrin receptor, which is important in iron transport, and mutations in HFE decrease the protein’s affinity for the receptor, impairing iron transport and resulting in iron overload. The classic clinical features of hemochromatosis include hepatic cirrhosis, cardiomyopathy, diabetes mellitus, pituitary dysfunction, hypogonadism, skin pigmentation, and sicca syndrome. Symmetrical arthropathy of the second and third metacarpal joints is a disabling complication that occurs in approximately 50% of patients. Radiographic manifestations are similar to those of osteoarthritis (see Chapter 88) and include characteristic “bird-beak” osteophytes arising from the radial side of the metacarpal. In addition, the presence of chondrocalcinosis can be seen in the wrists, as hemachromatosis is associated with calcium pyrophosphate deposition disease. Occasionally, superimposed attacks of pseudogout dominate the clinical picture. Osteoarthritis-like disease occurring in a middle-aged man with involvement of the metacarpophalangeal joints should indicate the possibility of hemochromatosis. Joint changes are irreversible. The diagnosis may be established with the identification of the mutated gene sequence in DNA obtained from peripheral blood.

Chapter 90—Rheumatic Manifestations of Systemic Disorders

PRIMARY BILIARY CIRRHOSIS Primary biliary cirrhosis is an inflammatory disease of the intrahepatic bile ducts that is frequently associated with other disorders presumed to be autoimmune, including limited scleroderma (see Chapter 83), rheumatoid arthritis (see Chapter 79), Sjögren syndrome (see Chapter 85), autoimmune thyroiditis, and renotubular acidosis. Approximately 90% of patients have detectable immunoglobulin G–antimitochondrial antibodies, which are rare in other forms of liver disease. Up to 50% of patients with primary biliary cirrhosis have secondary Sjögren syndrome, which represents the most common rheumatic disorder associated with primary biliary cirrhosis. Other musculoskeletal complications include (1) osteomalacia caused by reduced vitamin D absorption and (2) accelerated osteoporosis. The diagnosis of primary biliary cirrhosis should be suggested in the patient with unexplained pruritus or elevated levels of serum alkaline phosphatase. A positive antimitochondrial antibody test provides strong evidence, which should then be confirmed with a liver biopsy.

Endocrine Disorders DIABETES Many musculoskeletal complications of diabetes exist (Table 90-2). One of the most common complications is the socalled diabetic stiff-hand syndrome, which is characterized by waxy thickening of the skin in long-standing type 1 or 2 diabetes. Occasionally, it may develop before the onset of overt diabetes and may create confusion because of the similarity of its appearance to that of scleroderma-like sclerodactyly. These changes are thought to be the result of excess sugar alcohols, such as sorbitol, producing excess water content in the skin and leading to increased stiffness. Joint contractures, flexor tendon contractures (including Dupuytren contractures), and joint thickening produce a condition known as diabetic cheiroarthropathy or the syndrome of limited joint mobility; these conditions appear to be related to the duration of diabetes. Although it is most common in the fingers, limited mobility may also occur in the shoulders. Diabetic periarthritis of the shoulders also referred to as adhesive capsulitis or frozen shoulder. It occurs in 10% to 30% of patients with diabetes mellitus and typically affects patients with non–insulin-requiring diabetes of long duration. About half the patients have bilateral involvement, although, curiously, the nondominant shoulders frequently are more severely involved. In many instances, adhesive capsulitis in diabetics can remit spontaneously in several weeks. When adhesive capsulitis is accompanied by vasomotor changes of the same upper extremity, this can be referred to as shoulder-hand syndrome, which is similar to reflex sympathetic dystrophy. Charcot joints or neuropathic arthropathy may occur with any neuropathy but are most commonly associated with diabetes, although defects are present in less than 1% of all patients with diabetes. The condition affects men and women with equal frequency. Most patients are over age 40 years and have long-standing disease. Poorly controlled diabetes associated with diabetic peripheral neuropathy is the strongest risk factor. Tarsal and tarsometatarsal joints

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Table 90-2 Musculoskeletal Manifestations of Endocrine Disease Endocrine Disease Diabetes mellitus

Hypothyroidism

Hyperthyroidism

Hyperparathyroidism

Hypoparathyroidism

Acromegaly

Cushing syndrome

Musculoskeletal Manifestation Carpal tunnel syndrome Charcot arthropathy Adhesive capsulitis Syndrome of limited joint mobility (cheiroarthropathy) Diabetic amyotrophy Diabetic muscle infarction Proximal myopathy Arthralgias Joint effusions Carpal tunnel syndrome Chondrocalcinosis Myopathy Osteoporosis Thyroid acropachy Myopathy Arthralgias Erosive arthritis Chondrocalcinosis Muscle cramps Soft tissue calcifications Spondyloarthropathy Carpal tunnel syndrome Myopathy Raynaud phenomenon Back pain Premature osteoarthritis Myopathy Osteoporosis Avascular necrosis

are most commonly involved, and trauma together with diminished pain perception, proprioception, and position sense are major factors in the genesis of this arthropathy. The most common presentation is swelling of the foot with little or no pain. Treatment consists of avoiding weightbearing activities and application of a Charcot boot or soft cast. Prevention of skin oral ulceration over bony prominences is critical. End-stage Charcot deformity of the foot is referred to as “rocker-bottom feet.” Carpal tunnel syndrome is associated with diabetes. Up to 15% of all patients with carpal tunnel syndrome have diabetes. The condition causes typical paresthesias in median nerve distribution. Diffuse idiopathic skeletal hyperostosis occurs in approximately 20% of non–insulin-requiring diabetic patients. Typically patients have neck and back stiffness associated with loss of motion. Pain tends not to be prominent. Spine radiographs demonstrating calcification of the anterior longitudinal ligament of four contiguous vertebrae are diagnostic. Lack of involvement of the apophyseal joints distinguishes this disorder from ankylosing spondylitis and osteoarthritis. Physical therapy and nonsteroidal anti-inflammatory medications are the mainstays of treatment.

HYPOTHYROIDISM Almost one third of patients with frank hypothyroidism can exhibit objective musculoskeletal findings. Myxedematous

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arthropathy usually affects large joints. Patients may demonstrate swelling and stiffness, synovial membrane thickening, ligamentous laxity, and joint effusions. Synovial fluid is noninflammatory. In addition, hypothyroidism is associated with carpal tunnel syndrome, Raynaud phenomena, fibromyalgia-like muscle pain, and proximal muscle weakness with stiffness and increased creatinine kinase. Pseudogout may also be a presenting manifestation of hypothyroidism. Myopathy, especially proximal, occurs in hypothyroidism and is often associated with elevated levels of creatine kinase. Muscle biopsy specimens show atrophy of type II fibers but no inflammation. Thyroid replacement results in gradual improvement of both the arthropathy and myopathy of hypothyroidism.

arthritis-like disorder has also been described with involvement of the knees, wrists, hands, and shoulders, showing radiographic erosions. In contrast to rheumatoid arthritis, however, synovial proliferation is absent, the joint space is preserved, and erosions are characteristically on the ulnar side, as opposed to rheumatoid arthritis, in which the erosions are typically on the radial side. Secondary hyperparathyroidism is common in patients with chronic renal failure and is a component of renal osteodystrophy. Musculoskeletal features are similar to those described earlier.

HYPERTHYROIDISM

Sarcoidosis is a multisystemic inflammatory disorder exhibited by the formation of noncaseating granulomas. It may be associated with both acute and chronic rheumatic manifestations. The acute syndrome is known as Löfgren syndrome and consists of the classic triad of hilar adenopathy, erythema nodosum, and arthritis. It occurs in approximately 15% of those patients with sarcoidosis. The arthritis is usually symmetrical and migratory; it frequently involves the ankles, although it may be difficult to distinguish from erythema nodosum and peri-arthritis of the ankle. Joint effusions are typically noninflammatory. The arthritis is nondeforming, nonerosive, and self-limiting, usually not lasting more than 3 to 4 months. Patients with the nonarticular manifestations of Löfgren syndrome have an excellent prognosis. Chronic arthropathy involving the knees, ankles, wrists, and elbows occurs less frequently and is generally associated with active multisystemic disease. Synovial thickening and effusions are common; a synovial biopsy specimen may show the typical noncaseating granulomas. Treatment of acute sarcoid arthropathy includes the use of nonsteroidal anti-inflammatory drugs or, occasionally, a short course of corticosteroids. Treatment of the chronic arthropathy is dependent on the severity of the extra-articular manifestations that usually accompany it. Corticosteroids and other immunosuppressive agents are generally needed to control the systemic disease, which in turn can control the arthropathy. Bony involvement by sarcoidosis leads to lytic lesions, particularly over the phalanges, and can cause a pathologic fracture.

Four principal rheumatic manifestations occur in thyrotoxicosis: proximal myopathy, shoulder periarthritis, thyroid acropachy (thickened skin with periosteal new bone formation), and osteoporosis. Myopathy is common, occurring in 70% of patients with hyperthyroidism, but it is seldom a presenting manifestation. Myopathy tends to be more common in elderly patients with apathetic hyperthyroidism. The concurrence of new onset atrial fibrillation should be a clue. Periarthritis of the shoulder (especially bilateral) occurs in up to 10% of patients. Thyroid acropachy is a rare complication of Graves disease and consists of clubbing and soft tissue swelling of the hands and feet. Radiographs show periosteal new bone formation, which is best seen on the radial aspect of the second and third metacarpals. It is strongly associated with ophthalmopathy and pretibial myxedema. The symptoms of thyroid acropachy occur as patients achieve euthyroidism. Osteoporosis is produced by increased bone turnover, which accompanies the hyperthyroid state.

HYPERPARATHYROIDISM Musculoskeletal manifestations are common in hyperparathyroidism and are the initial manifestations in up to 15% of patients. Pseudogout is the most common rheumatic complication, occurring in up to 10% of patients with hyperparathyroidism, although radiographic chondrocal cinosis is seen in up to 40% of patients. A rheumatoid,

Sarcoidosis

Prospectus for the Future The future of recognizing rheumatic syndromes as part of systemic diseases relies on accurate diagnosis. With the employment of new cell-based assays, autoantibody tests, and physician recognition, the recognition of systemic disease with rheumatic manifestations can be facilitated. In addition, increasing the rheumatology workforce allows for rapid refer-

References Cagliero E, Apruzzese W, Perlmutter GS, Nathan DM: Musculoskeletal disorders of the hand and shoulder in patients with diabetes mellitus. Am J Med 112:487-490, 2002. Gertz MA, Comenzo R, Falk RH, et al: Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): A consensus

ral of patients who have rheumatic complaints that may be secondary to other systemic disorders, which in turn may lead to earlier diagnosis. Lastly, interdisciplinary care, such as in Centers of Excellence, allows for rapid referral among subspecialists when the diagnosis is in question.

opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol 79:319-328, 2005 Simms RW: Less common arthropathies—hematologic and malignant disorders. In Klippel JH (ed): Primer on the Rheumatic Diseases, 12th ed. Atlanta, Arthritis Foundation, 2001, pp 431-434.

Section XVII Infectious Disease

91 92 93 94 95 96 97 98 99

100

Organisms That Infect Humans –

RODRÍGUEZ *

LEDERMAN

Host Defenses Against Infection –

RODRÍGUEZ *

LEDERMAN

Laboratory Diagnosis of Infectious Diseases – RODRÍGUEZ * LEDERMAN

Antimicrobial Therapy – RODRÍGUEZ * LEDERMAN Fever and Febrile Syndromes – LEMONOVICH * SALATA Bacteremia and Sepsis Syndrome – WATKINS * SALATA Infections of the Nervous System – FULTON * SALATA Infections of the Head and Neck – LANGE * LEDERMAN Infections of the Lower Respiratory Tract – LANGE * LEDERMAN

Infections of the Heart and Blood Vessels – RODRÍGUEZ * LEDERMAN

101 102

Skin and Soft Tissue Infections – LANGE * LEDERMAN Intra-Abdominal Abscess and Peritonitis – LANGE *

103 104

Infectious Diarrhea – LANGE * LEDERMAN Infections Involving Bones and Joints –

105 106

Infections of the Urinary Tract – LANGE * LEDERMAN Health Care–Associated Infections – RAY * LISGARIS *

107

Sexually Transmitted Infections –

LEDERMAN LANGE *

LEDERMAN

SALATA HILEMAN * ARMITAGE

* SALATA

108

Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome – BECKWITH *

109

Infections in the Immunocompromised Host –

110

WING * RODRÍGUEZ * LEDERMAN LEMONOVICH * BOBAK * SALATA

Infectious Diseases of Travelers: Protozoal and Helminthic Infections – FAIRLEY * ARMITAGE * SALATA

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Organisms That Infect Humans Benigno Rodríguez and Michael M. Lederman

O

f diseases affecting humans, most that are curable and preventable are caused by infectious agents. The infectious diseases that capture the attention of physicians and the public periodically shift—for example, from syphilis to tuberculosis to acquired immunodeficiency syndrome (AIDS)—but the challenges of dealing with these processes endure. To the student, an understanding of infectious diseases offers insights into medicine as a whole. Osler’s adage (with updating) remains relevant: “He [or she] who knows syphilis [AIDS], knows medicine.”

Viruses Viruses produce a wide variety of clinical illnesses. A virus consists of either DNA or RNA (in rare cases, both) wrapped within a protein nucleocapsid. The nucleocapsid may be covered by an envelope composed of glycoproteins and lipids; pathogenic viruses that lack an envelope tend to survive better in the environment and are more often transmitted by the fecal-oral route, whereas those that possess an envelope are more often transmitted by the parenteral route or through the genital or respiratory mucosae. Viral genes can code for only a limited number of proteins, and viruses possess no metabolic machinery. They are entirely dependent on host cells for protein synthesis and replication and are therefore obligate intracellular parasites. Some viruses are dependent on other viruses to replicate or produce active infection. Such is the case with the delta agent, which produces disease only in the presence of hepatitis B infection. All must attach to receptors on the host cell and achieve entry into the cell through mechanisms that include receptor-mediated endocytosis, fusion, pinocytosis, or, in the case of certain nonenveloped viruses, direct penetration of the cell membrane. Once within the cells, the virus uncoats, allowing its nucleic acid to use host cellular machinery to reproduce (productive infection) or to integrate into the host cell (latent infection). Some viruses, such as influenza virus, cause disease by lysis of infected cells. Others, such as hepatitis B virus, do not directly cause cell destruction 884

but may involve the host immune responses in the pathogenesis of disease. Still others, such as the human T-lymphotropic virus type 1, promote neoplastic transformation of infected cells. Viruses have developed several mechanisms for evading host defense mechanisms. By multiplying within host cells, viruses can avoid neutralizing antibodies and other extracellular host defenses. Some viruses can spread to uninfected cells by intercellular bridges. Others, especially the herpes group and human immunodeficiency virus (HIV), are capable of persisting latently without multiplication in a metabolically inactive form within host cells for prolonged periods. The influenza virus is capable of extensive gene rearrangements, resulting in significant changes in surface antigen structure. This allows new strains to evade host antibody responses directed at earlier strains. Some viruses, as they exit the host cell during productive infection, may carry antigens of host cell origin, thus providing another potential mechanism for evading host defenses, whereas others block host immune defense mechanisms (such as expression of human leukocyte antigens). HIV induces both specific and nonspecific escape mechanisms by selectively deleting HIV-reactive T-cell clones and coating itself with a host-derived “glycan shield” that hinders neutralizing antibody attachment, while also causing profound global immune dysfunction that paralyzes host defenses.

Prions Prions are a group of host-encoded transmissible proteins devoid of nucleic acid material that cause disease through accumulation of a pathogenic isoform of the prion protein. They are thought to be responsible for a number of progressive and ultimately fatal neurologic diseases in humans, including kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome and familial fatal insomnia, and animal diseases such as scrapie and bovine spongiform encephalopathy (“mad cow disease”). Although some prion diseases (e.g., familial CJD) are inherited, others,

Chapter 91—Organisms That Infect Humans including kuru and new variant CJD, are acquired through consumption of infected neural tissue. There is no known treatment for these disorders.

Bacteria Bacteria comprise a tremendously varied group of organisms that are generally capable of cell-free growth, although some produce disease as intracellular parasites. There are numerous ways of classifying bacteria, including morphology, ability to retain certain dyes, growth in different physical conditions, ability to metabolize various substrates, and antibiotic sensitivities. Although combinations of these methods are used to identify bacteria in clinical bacteriology laboratories, relatedness for taxonomic purposes is established by DNA homology.

CHLAMYDIAE Chlamydiae are obligate intracellular parasites; they always contain both DNA and RNA, divide by binary fission (rather than multiplying by assembly), can synthesize proteins, and contain ribosomes. Although classified as a unique family of bacteria, they are unable to synthesize adenosine triphosphate and thus depend on energy from the host cell to survive. The three chlamydial species known to cause disease in humans are Chlamydia trachomatis, Chlamydophila pneumoniae, and Chlamydia psittaci. C. trachomatis causes trachoma, the major cause of blindness in the developing world, and a variety of sexually transmitted genitourinary disorders, including urethritis, salpingitis, and lymphogranuloma venereum. C. pneumoniae is a common cause of atypical pneumonia, bronchitis, and sinusitis. C. psittaci, the cause of a common infectious disease of birds, can produce a serious systemic illness with prominent pulmonary manifestations in humans. Chlamydiae are susceptible to tetra cyclines, rifampin, macrolides and related compounds, ketolides, and certain quinolones.

RICKETTSIAE AND EHRLICHIAE Rickettsiae and ehrlichiae are also small bacterial organisms that, like chlamydiae, are obligate intracellular parasites. They are primarily animal pathogens that generally produce disease in humans through the bite of an insect vector, such as a tick, flea, louse, or mite. Most of these organisms specifically infect vascular endothelial cells. With the exception of Q fever and human ehrlichiosis, rash caused by vasculitis is a prominent manifestation of these often disabling febrile illnesses. These organisms are susceptible to tetracyclines and chloramphenicol.

MYCOPLASMAS Mycoplasmas are the smallest free-living organisms. In contrast to viruses, chlamydiae, rickettsiae, and ehrlichiae, mycoplasmas can grow on cell-free media and produce disease without intracellular penetration. Like other bacteria, these organisms have a membrane, but unlike other bacteria, they have no cell walls. Thus antibiotics that are active against bacterial cell walls have no effect on mycoplas-

885

mas. At least 14 species of mycoplasma may cause disease in humans. Mycoplasma pneumoniae is an agent of pharyngitis and pneumonia. Although Mycoplasma hominis, Ureaplasma urealyticum, and the newly described Mycoplasma genitalium are primarily agents of genitourinary disease, they may also cause systemic infections, particularly in compromised hosts. Mycoplasmas are sensitive to erythromycin, tetracycline, a combined regimen of both, and most quinolones.

SPIROCHETES Spirochetes are slender, motile, spiral organisms that are not readily seen under the microscope unless stained with silver or viewed under darkfield illumination. Many of these organisms cannot yet be cultured on artificial media or in cell culture. Four genera of spirochetes cause disease in humans. Treponema species include the pathogens of syphilis and the nonvenereal, endemic, syphilis-like illnesses of yaws, pinta, and bejel. The illnesses caused by these organisms are chronic and characterized by prolonged latency in the host. Penicillin is active against Treponema. Leptospira species are the causative agents of leptospirosis, an acute or subacute febrile illness occasionally resulting in aseptic meningitis, jaundice, and (in rare cases) renal insufficiency. Borrelia species are arthropod-borne spirochetes that are the causative agents of Lyme disease (see Chapter 95) and relapsing fever. During afebrile periods in relapsing fever, these organisms reside within host cells and emerge with modified cell surface antigens. These modifications may permit the bacterium to evade host immune responses and produce relapsing fever and recurrent bacteremia. Spirillum minus is one of the causative agents of rat-bite fever. Helicobacter pylori is a spirochete of the upper gastrointestinal tract that plays an important role in the pathogenesis of duodenal and gastric ulcers and also in certain neoplasms of the gastrointestinal tract.

ANAEROBIC BACTERIA Anaerobes are organisms that cannot grow in atmospheric oxygen tensions. Some are killed by very low oxygen concentrations, whereas others are relatively aerotolerant. As a general rule, anaerobes that are pathogens for humans are not as sensitive to oxygen as nonpathogens. Anaerobic bacteria are primarily commensals. They inhabit the skin, gut, and mucosal surfaces of all healthy individuals. In fact, the presence of anaerobes may inhibit colonization of the gut by virulent, potentially pathogenic bacteria. Anaerobic infections generally occur in two circumstances: • Contamination of otherwise sterile sites with anaerobeladen contents. Examples include (1) aspiration of oral anaerobes into the bronchial tree, producing anaerobic necrotizing pneumonia; (2) peritonitis and intraabdominal abscesses after bowel perforation; (3) fasciitis and osteomyelitis after odontogenic infections or oral surgery; and (4) some instances of pelvic inflammatory disease. • Infections of tissue with lowered redox potential as the result of a compromised vascular supply. Examples include (1) foot infections in diabetic patients, in whom vascular disease may produce poor tissue oxygenation; and (2)

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Section XVII—Infectious Disease

infections of pressure sores, in which fecal anaerobic flora gain access to tissue whose vascular supply is compromised by pressure. The pathogenesis of anaerobic infections—that is, soilage by a complex flora—generally results in polymicrobial infections. Thus the demonstration of one anaerobe in an infected site generally implies the presence of others. Often, facultative organisms (organisms capable of anaerobic and aerobic growths) coexist with anaerobes. Certain anaerobes, such as Clostridium, produce toxins that cause well-defined systemic illnesses such as food poisoning, tetanus, and botulism. Other toxins may play a role in soft tissue infections (cellulitis, fasciitis, and myonecrosis) occasionally produced by Clostridium species. Clostridium difficile is the causative agent of pseudomembranous colitis, a diarrheal disease of varying severity (sometimes fatal) that has emerged as a major cause of morbidity in patients receiving antibiotic therapy and those in health care facilities. Bacteroides fragilis, the most numerous bacterial pathogen in the normal human colon, has a polysaccharide capsule that inhibits phagocytosis and promotes abscess formation. Clues to the presence of anaerobic infection include a foul odor; the presence of gas, which may be seen radiographically or manifested by crepitus on examination (although not all gas-forming infections are anaerobic); and the presence of mixed grampositive and gram-negative flora on a Gram stain of purulent exudate, especially when there is little or no growth on plates cultured aerobically. Many pathogenic anaerobes are sensitive to penicillin. Exceptions are strains of B. fragilis (usually sensitive to metronidazole, clindamycin, or ampicillin-sulbactam) and C. difficile (which is almost always sensitive to metronidazole and vancomycin). Strains of Fusobacterium may also be relatively resistant to penicillin. As a general rule, infections caused by anaerobes originating from sites above the diaphragm are more often (but not always) penicillin sensitive, whereas infections below the diaphragm are often caused by penicillin-resistant organisms, notably B. fragilis.

GRAM-NEGATIVE BACTERIA The cell walls of gram-negative bacteria, which appear pink on a properly prepared Gram stain, contain lipopolysaccharide, a potent inducer of cytokines such as tumor necrosis factor, and are associated with fever and septic shock. These organisms cause a wide variety of illnesses. Gram-negative bacteria are the most common cause of cystitis and pyelonephritis. Haemophilus species are common pathogens of the respiratory tract and cause otitis media, sinusitis, tracheobronchitis, and pneumonia. Lower respiratory tract infections with these organisms are particularly common in adults with chronic obstructive pulmonary disease. Haemophilus can be an important cause of meningitis, particularly in children. Except for Haemophilus and Klebsiella species, gram-negative bacteria are uncommon causes of community-acquired pneumonia but are common causes of nosocomial pneumonia. Except for the peculiar risk of Pseudomonas infection in intravenous drug users, gram-negative organisms are rare causes of endocarditis on natural heart valves but are occasional pathogens on prosthetic valves. The Enterobacteria-

ceae include Escherichia coli, Klebsiella, Enterobacter, Serratia, Salmonella, Shigella, and Proteus. These are large gramnegative rods. Except for the occasional presence of a clear space surrounding some Klebsiella representing a large capsule, these organisms are not readily distinguished from one another on Gram stain. The Enterobacteriaceae can be thought of as gut-related or genitourinary pathogens. Salmonella, a relatively common cause of enteritis, may occasionally infect atherosclerotic plaques or aneurysms. Shigella is an agent of bacterial dysentery. Proteus species, which split urea, are the agents associated with staghorn calculi of the urinary collecting system. Increasingly, gramnegative bacteria that are often resistant to multiple antibiotics are important causes of nosocomial infection. The genus Bartonella contains a group of emerging pathogens that cause uncommon, unique infections including bacillary angiomatosis, cat-scratch disease, and South American bartonellosis. Gram-negative cocci that cause disease in humans include Neisseria and Moraxella species. These kidney bean–shaped diplococci are not distinguishable from one another on Gram stain. Neisseria meningitidis is an important cause of meningitis, and Neisseria gonorrhoeae causes gonorrhea. Moraxella catarrhalis, which is part of the normal oral flora, is a cause of lower respiratory tract infection.

GRAM-POSITIVE BACTERIA Although these organisms (which appear deep purple on Gram stain) lack endotoxin, infections with gram-positive bacteria also produce fever and cannot be reliably distinguished on clinical grounds from infections caused by gramnegative bacteria.

Gram-Positive Rods Infections caused by gram-positive rods are relatively uncommon outside certain specific settings. Diphtheria is rare (although epidemics have occurred in recent years), but other corynebacteria produce infections in the immunocompromised host and on prosthetic valves and shunts. Because corynebacteria are regular skin colonizers, they often contaminate blood cultures; in the appropriate setting, however, they must be considered potential pathogens. Listeria monocytogenes resembles Corynebacterium on initial isolation, and this food-borne pathogen is an increasingly important cause of meningitis and bacteremia in the immunocompromised patient. Bacillus cereus is a recognized cause of food poisoning. Serious infections with this and other Bacillus species occur among intravenous drug users. Infections with Clostridium species were discussed earlier.

Gram-Positive Cocci Staphylococcus aureus is a common pathogen that can infect any organ system. It is a common cause of bacteremia and sepsis. The organism often colonizes the anterior nares, particularly among insulin-treated diabetics, hemodialysis patients, and injection drug users; these populations therefore have a greater frequency of infections with this organism. Hospital workers colonized with S. aureus have been responsible for hospital epidemics of staphylococcal disease. Generally protected by an antiphagocytic polysaccharide capsule, staphylococci also possess catalase, which inacti-

Chapter 91—Organisms That Infect Humans vates hydrogen peroxide—a mediator of bacterial killing by neutrophils. Staphylococci tend to form abscesses; the low pH within an abscess cavity also limits the effectiveness of host defense cells. Staphylococci elaborate several toxins that mediate specific manifestations of disease. A staphylococcal enterotoxin is responsible for staphylococcal food poisoning. Staphylococcal toxins also mediate the scalded skin syndrome and the multisystem manifestations of toxic shock syndrome. Most staphylococci are penicillinase producing, and an increasing proportion are resistant to penicillinase-resistant penicillin analogues. Although commonly referred to as methicillin-resistant S. aureus (MRSA), they are resistant to all β-lactams. Once found almost exclusively in hospitalized patients, MRSA strains that express novel pathogenic determinants, such as the Panton-Valentine leukocidin (PVL), and exhibit a distinctive antimicrobial resistance pattern have now become established in the community and are the cause of thousands of severe communityacquired infections each year. At the same time, the role of MRSA as a nosocomial pathogen continues, and MRSA has been responsible for widespread epidemics in health care institutions worldwide. Vancomycin remains active against most strains, but strains with reduced susceptibility and even complete resistance to this and other glycopeptides have recently been isolated from clinical cases. Resistance in these strains is the result of acquisition of mobile genetic elements from Enterococcus species, likely in the hospital setting. These strains are still uncommon but can cause severe disease, including bloodstream infections. Strains with decreased susceptibility to the oxazolidinone linezolid have now also been described. Other staphylococci are distinguished from S. aureus primarily by their inability to produce coagulase. Some of these coagulase-negative staphylococci produce urinary tract infection (Staphylococcus saprophyticus). Another, Staphylococcus epidermidis, is part of the normal skin flora and an increasingly important cause of infection on foreign bodies such as prosthetic heart valves, ventriculoatrial shunts, and intravascular catheters. Like Corynebacterium, S. epidermidis may be a contaminant of blood cultures but in the appropriate setting should be considered a potential pathogen. S. saprophyticus is sensitive to a variety of antibiotics used in the treatment of urinary tract infection; S. epidermidis is usually resistant to all β-lactams but sensitive to vancomycin. Streptococci are classified into groups according to the presence of serologically defined carbohydrate capsules (Lancefield typing). Group A streptococci produce skin infections, pharyngitis, and systemic infections. These organisms are also associated with the immunologically mediated poststreptococcal disorders—glomerulonephritis and acute rheumatic fever. Streptococci are further classified according to the pattern of hemolysis on blood agar—α for incomplete hemolysis (producing a green discoloration on the agar), β for complete hemolysis, and γ for nonhemolytic strains. An important α-hemolytic species is Streptococcus pneumoniae (pneumococcus), the most common cause of community-acquired pneumonia and an important cause of meningitis and otitis media. Penicillin resistance in pneumococcal isolates is an increasingly important problem and is often associated with concomitant resistance to other agents. Whereas pneumococcal pneumonia caused by

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strains with intermediate penicillin resistance can still be successfully treated with very high doses of penicillin, other antimicrobial agents must now be used for pneumococcal meningitis (see Chapter 97). Penicillin-resistant S. pneumoniae generally remains susceptible to vancomycin. A heterogeneous group of streptococci, often improperly referred to as viridans (green) streptococci (these organisms may show α- or γ-hemolysis), includes several species of streptococcus that are common oral or gut flora and are important agents of bacterial endocarditis, abscesses, and odontogenic infections. Formerly classified as members of the Streptococcus genus, enterococci are facultative anaerobes that, unlike the streptococci, exhibit variable degrees of resistance to penicillins and are uniformly resistant to cephalosporins. Vancomycinresistant strains of enterococci are increasingly prevalent causes of serious hospital-acquired infections, particularly in immunocompromised and postsurgical patients, that are exceedingly difficult to treat.

MYCOBACTERIA Mycobacteria comprise a group of rod-shaped bacilli that stain weakly gram positive. These organisms are rich in lipid content and are recognized in tissue specimens by their ability to retain dye after washing with acid alcohol (acid fast). These bacteria are generally slow-growing (some require up to 6 weeks to demonstrate growth on solid media), obligate aerobes. They generally produce chronic disease and survive for years as intracellular parasites of mononuclear phagocytes. Some escape intracellular killing mechanisms by blocking phagosome and lysosome fusion or by disrupting the phagosome. Almost all provoke cell-mediated immune responses in the host, and clinical disease expression may be related in large part to the nature of the host immune response. Tuberculosis is caused by Mycobacterium tuberculosis. Other mycobacteria (nontuberculous mycobacteria) can cause diseases resembling tuberculosis. Certain rapid-growing mycobacteria cause infections after surgery or implantations of prostheses, as well as epidemic and sporadic skin and soft tissue infections. Mycobacterium avium complex (MAC) is an important cause of disseminated infection among patients with AIDS. MAC is frequently resistant to drugs usually used in the treatment of tuberculosis. Leprosy is a mycobacterial disease of skin and peripheral nerves caused by the noncultivatable Mycobacterium leprae.

ACTINOMYCETALES Nocardia and Actinomyces are weakly gram-positive filamentous bacteria. Nocardia is acid fast and aerobic; Actinomyces is anaerobic and not acid fast. Actinomyces inhabits the mouth, gut, and vagina and produces cervicofacial osteomyelitis and abscess, pneumonia with empyema, and intraabdominal and pelvic abscess, the last often associated with intrauterine contraceptive devices. Nocardia most commonly produces pneumonia and brain abscess. Approximately half of patients with Nocardia infection have underlying impairments in cell-mediated immunity. Infections with either of these slow-growing organisms require long-term treatment. Actinomyces is relatively sensitive to

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many antibiotics; penicillin is the treatment of choice. Nocardia infections are treated with high doses of sulfonamides, but serious or resistant infections may require combinations of carbapenems, aminoglycosides, and cephalosporins.

Fungi Fungi are larger than bacteria. Unlike bacteria, they have rigid cell walls that contain chitin as well as polysaccharides. They grow and proliferate by budding, by elongation of hyphal forms, and/or by spore formation. Except for Candida and related species, fungi are rarely visible on Gram-stained preparations but can be stained with Gomori methenamine silver stain. They are also resistant to potassium hydroxide and can often be seen on wet mounts of scrapings or secretions to which several drops of a 10% solution of potassium hydroxide have been added. Fungi are resistant to most antibiotics used in the treatment of bacterial infections and are typically treated with drugs active against their unusual cell wall. Most fungi can exist in a yeast form (round to ovoid cells that may reproduce by budding) and a mold form, a complex of tubular structures (hyphae) that grow by branching or extension. Candida species are oval yeasts that often colonize the mouth, gastrointestinal tract, and vagina of healthy individuals. They may produce disease by overgrowth and/ or invasion. Candida stomatitis (thrush) often occurs in individuals who are receiving antibiotic or corticosteroid therapy or who have impairments of cell-mediated immunity. Vulvovaginitis caused by Candida may occur in these same settings but can also occur in women with no apparent predisposing factors and more commonly in women with diabetes mellitus. Candida can also colonize and infect the urinary tract, particularly in the presence of an indwelling urinary catheter. Candida species may also gain entry into the bloodstream and produce fungemia with or without seeding of solid tissues, especially in hospitalized patients, in whom Candida species are now the fourth leading cause of intravascular infection. This most frequently occurs in the setting of neutropenia after chemotherapy, where the portal of entry is the gastrointestinal tract, or in individuals with intravascular catheters, which provide a route for cutaneous Candida to enter the systemic circulation (see Chapter 106). Largely as a consequence of widespread use of empiric and targeted antibiotic therapy, as well as more frequent immunosuppressive conditions, Candida species other than Candida albicans have become increasingly common causes of invasive disease in hospitals. These non–C. albicans species (e.g., Candida glabrata, Candida krusei, Candida tropicalis) are more often resistant to commonly used antifungals such as fluconazole and have therefore skewed the landscape of empiric antifungal therapy, especially in immunosuppressed patients, toward broader-spectrum agents such as amphotericin B and the echinocandins. Histoplasma capsulatum is a dimorphic fungus endemic to the Ohio and Mississippi River valleys that produces asymptomatic infection or a mild febrile syndrome in most individuals and a self-limited pneumonia in some. In predisposed individuals, it can cause cavitary pulmonary disease

and mediastinal fibrosis. Infants and immunosuppressed individuals, such as those with AIDS or neutropenia, are susceptible to the progressive disseminated form of the infection, which is potentially fatal (see Chapter 108). Systemic or progressive disease is treated with parenteral amphotericin B or itraconazole. The dimorphic fungus Coccidioides immitis is endemic in the southwestern United States and, like H. capsulatum, produces a self-limited respiratory infection or pneumonia in most infected individuals. Immunocompromised individuals are at greatest risk for fatal systemic dissemination or meningitis. Fluconazole, itraconazole, or amphotericin B is used for progressive or extrapulmonary disease. Cryptococcus neoformans is a yeast with a large polysaccharide capsule. It produces a self-limited or chronic pneumonia, but the most common clinical manifestation of infection with this fungus is a chronic meningitis. Although patients with impairment in cell-mediated immunity are at risk for cryptococcal meningitis, some patients with this syndrome have no identifiable immunodeficiency. Treatment is with amphotericin B combined with flucytosine. Long-term oral fluconazole therapy is effective in preventing relapse in persons with AIDS (see Chapter 108). Blastomyces dermatitidis is a dimorphic organism also endemic in the Ohio and Mississippi River basins. Acute self-limited pulmonary infection is followed in rare instances by disseminated disease. Skin disease is most common, but bones, the central nervous system, and the genitourinary tract may be involved as well. Amphotericin B is used for treating systemic disease; itraconazole is appropriate for immunocompetent hosts. Aspergillus is a mold that produces several clinical illnesses in humans. Acute bronchopulmonary aspergillosis is an immunoglobulin E–mediated hypersensitivity to Aspergillus colonization of the respiratory tract. This condition produces wheezing and fleeting pulmonary infiltrates in patients with asthma. Occasionally, Aspergillus will colonize a preexistent pulmonary cavity and produce a mycetoma or fungus ball. Hemoptysis is the most serious complication of such infection. Invasive pulmonary aspergillosis is a rare cause of chronic illness in marginally compromised hosts; more often, it is a cause of acute, life-threatening pneumonia or disseminated infection in patients with neutropenia or in recipients of organ transplants. Voriconazole is now the drug of choice for most cases of invasive aspergillosis; amphotericin B and the echinocandins remain important alternatives or concomitant agents. The zygomycetes (Mucorales) are molds with ribbonshaped hyphae that produce disease in patients with poorly controlled diabetes mellitus or hematologic malignancy or in recipients of organ transplantation. Invasive disease of the palate and nasal sinuses, which may extend intracranially, is the most common presentation, but pneumonia may be seen as well. These infections are generally treated with surgical excision plus high-dose amphotericin B. Pneumocystis jiroveci (formerly Pneumocystis carinii) was once thought to be a protozoan; genetic analyses have classified P. jiroveci as a fungus. This organism causes life-threatening pneumonia in patients with impaired cell-mediated immunity; it is the most common major opportunistic pathogen in persons with AIDS (see Chapter 108).

Chapter 91—Organisms That Infect Humans

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Table 91-1 Some Protozoal Diseases of Humans Protozoan

Clinical Illness

Transmission

Diagnosis

Plasmodium Babesia microti Trichomonas vaginalis Toxoplasma gondii*

Mosquito, transfusion Tick, transfusion Sexual contact Raw meat, cat feces

Peripheral blood smear Peripheral blood smear Vaginal smear Serologies, tissue biopsy

Entamoeba histolytica Giardia lamblia

Malaria: fever, hemolysis Fever, hemolysis Vaginitis Fever, lymph node enlargement; encephalitis, brain abscess in compromised host Colitis, hepatic abscess Diarrhea, malabsorption

Fecal-oral Fecal-oral

Cryptosporidium*

Diarrhea

Fecal-oral

Isospora belli*

Diarrhea, malabsorption

Fecal-oral

Microsporidium*

Diarrhea, malabsorption, dissemination

Fecal-oral

Stool smear, serologies Stool smear, small bowel aspirate Sugar flotation, acid-fast stain of stool, biopsy Wet mount or acid-fast stain of stool Small bowel biopsy Electron microscopy

*Important opportunistic pathogens in persons with acquired immunodeficiency syndrome (see Chapter 108).

Protozoans The protozoal pathogens listed in Table 91-1 are all important causes of disease within the United States. Infections caused by these organisms are diagnosed as indicated in Table 91-1 and are discussed in the relevant disease-oriented chapters.

Helminths Diseases caused by helminths are among the most prevalent diseases in the developing world but are uncommon causes

of illness in North America. In contrast to the pathogens discussed previously, helminths are multicellular parasites. Helminthic pathogens found in the United States include the roundworm Ascaris species (maldigestion and obstruction), the hookworm Necator americanus (intestinal blood loss), the pinworm Enterobius vermicularis (anal pruritus), and the threadworm Strongyloides stercoralis (gastroenteritis and dissemination in the immunocompromised host). It is important to recognize the risk of other helminthic diseases in travelers returning from endemic regions (see Chapter 110).

Prospectus for the Future Clinicians should anticipate the identification of “novel” pathogens causing disease, as follows: • Prevalent microbes not previously recognized as pathogenic • “Discovery” of prevalent pathogens not previously identified

References Bruckner DA, Colonna P: Nomenclature for aerobic and facultative bacteria. Clin Infect Dis 29:713-723, 1999. Dermody TS, Tyler KL: Introduction to viruses and viral diseases. In Mandell GL, Bennett JE, Dolin R (eds): Principles and Practice of Infectious Diseases, 6th ed. Philadelphia, Elsevier, 2005, pp 1729-1742.

• Influx into new communities of pathogens prevalent elsewhere • Increased frequency and distorted clinical presentation of uncommon pathogens as a consequence of immunosuppressive conditions and treatments • Emergence of resistant strains of common pathogens

Summanen P: Microbiology terminology update: Clinically significant anaerobic gram-positive and gram-negative bacteria (excluding spirochetes). Clin Infect Dis 29:724-727, 1999.

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Chapter

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Host Defenses Against Infection Benigno Rodríguez and Michael M. Lederman

Host Defenses versus Mechanisms of Microbial Pathogenesis: The Struggle for Survival As our experience suggests and as fossil records indicate, life is a continuous struggle for survival. Pathogenic and host defense evasive mechanisms of microbes are countered by multiple and overlapping host innate and adaptive immune defense mechanisms. In some cases, the pathogen “wins,” with destruction of the host; in others, the host immune response prevails, with eradication of the microbe. Often there is a standoff characterized by latent infection or colonization without substantial morbidity to the host; sometimes the relationship is actually symbiotic, with both host and pathogen gaining from it. In settings of latent or colonizing pathogens, microbes have the capacity to activate and cause disease if host defenses become impaired. Much of our understanding of host defenses and their relationship to microbial pathogenesis has been derived from recognizing the spectrum of infections experienced by individuals with specific impairments of host defenses. Thus, persons with neutrophil depletion or defects in neutrophil function tend to experience bacterial and fungal infections, those with antibody defects are particularly at risk for infections caused by encapsulated bacteria, and persons with impairments in cell-mediated immunity tend to be at particular risk for infection with pathogens that replicate within host cells. Reflecting the importance of these insights, in the early days of the acquired immunodeficiency syndrome (AIDS) epidemic, astute clinicians recognized immediately that the kinds of infections seen in the first AIDS patients implicated an acquired impairment of cell-mediated adaptive immune defenses; this insight accelerated research on the pathogenesis and etiology of AIDS. 890

Evolutionary Advantage of Adaptable Organisms Fundamental to our understanding of evolution is the concept that organisms most capable of adaptation to environmental stresses are most likely to survive, to propagate, and to persist. Thus, random mutations in the germline that confer survival advantage are passed on to adapting, succeeding generations. With this in mind, it is astounding that complex organisms such as humans can compete for survival with microbes much more capable of rapid genetic adaptation to challenge. The number of germline mutations over time is dependent on generation time, the number of offspring per generation, and the mistake rate of the DNA or RNA polymerase required for genomic replication. In each of these indices, microbes have the clear adaptive advantage. As an example, humans must survive at least 10 years or more before they are even capable of reproduction, and then they generate only a small number of offspring before dying. In contrast, bacteria can grow exponentially, with generation times measured in minutes to hours, and viruses express thousands of progeny with replication cycles that can be completed within hours to days. Human DNA polymerases have an error rate of approximately one base pair per 1012 per cellular division; bacterial DNA polymerases have an error rate of approximately one base pair per 106, and the reverse transcriptase of human immunodeficiency virus type 1 (HIV-1) has an error rate of approximately one base pair per 103 to 104 per replication. These mutations are to a large extent random, and most result in decreased function or are incompatible with survival. Because of the limited number of offspring humans produce, a faithful DNA polymerase that maximizes survival of an individual’s descendants is important to our species. In contrast, microbes can generate many defective organisms with null mutations and still maintain a self-sustaining

Chapter 92—Host Defenses Against Infection population of organisms arising from the small subset that harbor the rare mutations that confer a survival advantage. The rapid emergence of resistance to antimicrobials is reflective of the genetic flexibility of microbes. The ability to recognize and respond nonspecifically to foreign organisms has existed for millions of years and can be demonstrated even in relatively primitive life forms. But to survive in the struggle for the environment against microbes and their seemingly unending ability to replicate and evolve over short intervals of time, more complex species (including humans) with slow and infrequent germline evolution events require a system that can efficiently adjust to protect the individual against the constantly changing onslaught of microbial pathogens. Thus, with the appearance of the gnathostomes, or jawed vertebrates, an adaptable immune defense system emerged that for the first time permitted a rapid “evolution” of host defense to infectious agents without the need for reproduction or germline mutation. This “real-time evolution” is achieved through rearrangement (and, in the case of B lymphocytes, somatic mutation) of the genes encoding the receptors of T and B lymphocytes and the ability to expand clones of these microbe-specific cells—the directors of adaptive immune recognition.

Categories of Host Defenses and Risks for Infection Over the course of species development, numerous mechanisms have evolved to protect larger organisms from infection or parasitization by another. These mechanisms can be categorized according to the primary defense mechanism as anatomic, humoral, or cellular, and according to their specificity and phylogenetics as innate or adaptive. Anatomic defenses are primarily innate or nonadaptive, whereas humoral and cellular defenses can be either innate or adaptive. Innate defenses, present in many primitive organisms, comprise a rapid, “already primed” response to microbial invasion, whereas adaptive responses may be more delayed in their onset but ultimately are both more specific in their targets and capable of providing “memory” of prior encounters to protect against recurrence of infection. Although it is important to distinguish between these two kinds of host defenses, both innate and adaptive immune mechanisms are intimately interactive, thereby providing, in most instances, remarkable synergistic protection against infection.

ANATOMIC DEFENSES Anatomic defenses protect directly against microbial colonization and infection and are primarily located at sites with proximate environmental contact. Thus skin and mucosal surfaces are enriched with defenses ranging from the tightness of epithelial junctions to resist microbial penetration, to the presence of cough and gag reflexes to expel aspirated secretions, and to the presence of chemical agents such as acids and defensins with antimicrobial properties. Permissiveness to colonization of these surfaces by microbes of low pathogenicity prevents colonization and infection by more

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virulent organisms. In some clinical settings, interference with anatomic defense mechanisms may increase the risk of infection. Therefore burns that denude the epithelial barrier, illnesses or intoxicants that suppress gag and cough reflexes, treatment with agents that decrease gastric pH, and treatment with antibiotics that disturb the commensal mucosal flora can increase the risks of microbial infection.

HUMORAL DEFENSES AGAINST INFECTION Complement System Humoral defenses, consisting of soluble compounds found in blood plasma and in other extracellular fluids, also play important roles in defense against microbes. One of the most important of these humoral defenses is the complement system. Complement activity results from the sequential interaction of a large number of plasma and cell membrane proteins. A simplified diagram of the most important steps in the complement cascade is shown in Figure 92-1. The classic complement pathway is activated by antibody-coated targets or antigen-antibody complexes through the interaction of the initial protein, C1, with the Fc receptor of the antigen-activated immunoglobulin (Ig) molecule The alternative pathway is activated in the absence of antibody by constituents of the microbial surface, including polysaccharides. Finally, the sugar-binding protein mannose-binding lectin can also activate the complement cascade after binding to surface mannose residues on viruses and other pathogens. All three pathways converge with the formation of C3 convertase, which leads to the production of the effector components of the complement system. C3b or iC3b deposited on the surface of microbes binds to complement receptors (CR1, CR3, and CR4) on neutrophils and macrophages and Alternate pathway

Classic pathway

Mannose-binding lectin pathway

Pathogen surface

Ag-Ab complexes, apoptotic cells

Mannosebinding lectin

C3 Factor B Factor D

C1 (q, r, s)

MASP-1, MASP-2

C4, C2

C3a, C5a (Inflammation, phagocyte chemotaxis)

C3 convertase

C5b, C6, C7, C8, C9 (Membrane attack complex, lysis of pathogens and other target cells)

C3b (Binding to complement receptors on phagocytes, phagocytosis and immune complex clearance enhancement)

Figure 92-1 Simplified diagram of the complement system. The final effector components are shown in clear symbols at the bottom of the graphic, with a summary of their most important biologic activities. Not all molecular events leading to the final effector components are shown.

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Table 92-1 Properties of Human Immunoglobulins H chain class Molecular weight (approximate) Complement fixation (classic) Opsonic activity (for binding) Reaginic activity Serum concentration (approximate mg/dL) Serum half-life (days) Major functions

IgG

IgA

IgM

IgD

IgE

γ 150,000

α 170,000

µ 900,000

δ 180,000

ε 190,000

++

0

++++

0

0

++++

++

0

0

0

0 1500

0 150-350

0 100-150

0 2

++++ 2

23 Recall response; opsonization; transplacental immunity

6 Secretory immunity

5 Primary response; complement fixation

3 ?

2.5 Allergy; anthelmintic immunity

promotes phagocytosis. Moreover, C3b furthers clearance of immune complexes by linking them to CR1 on the erythrocyte surface. C5a is a chemotaxin for neutrophils and activates oxidative burst activity. C5a and C3a also stimulate histamine release from mast cells and thus promote inflammation. The ultimate effector element of the complement system is the membrane attack complex, which involves C5 to C9. This complex produces pores in the membrane of microbes and subjects them to osmotic lysis. Thus, the complement system can opsonize microbes, can directly damage them, and can also induce inflammation through liberation of chemotactically active fragments. Persons with complement deficiencies, particularly deficiencies in terminal components, are especially at risk for repeated infections with gram-negative encapsulated bacteria, especially Neisseria species.

Antibodies Antibodies are large polypeptides produced by B lymphocytes and plasma cells that are key components of the adaptive immune response (Table 92-1). Antibody molecules recognize structural elements of microbial surfaces and, when bound, may block the ability of that structure to interact with and infect a cell (neutralization), may facilitate ingestion of the microbe by phagocytes (opsonization), or may bind and activate complement (discussed earlier), resulting in killing of certain microbes. Finally, antibodies may recognize microbial or other foreign antigens expressed on a cell surface and facilitate the destruction of that cell by host defense cells with cytolytic capabilities (antibodydependent cellular cytotoxicity [ADCC]). The five classes of antibodies are summarized in Table 92-1. IgM constitutes the earliest immune response to antigenic challenge and often predominates in response to polysaccharides; IgG is the most prevalent Ig class in blood; IgA is present both in blood and at mucosal surfaces and is a key element in mucosal immune protection; IgD and IgM may serve as B-lymphocyte antigen receptors; IgE plays an important role in allergy by triggering mast cell activation and is also important in mediating responses to parasitic infestation. As components of the adaptive immune response, antibodies have great diversity in their recognition domains, and the generation of this diversity permits both targeted investment of

immune “energy” and the generation of immune memory. Antibodies provide protection against microbes primarily when these organisms are in the extracellular space. Once within cells that they infect, microbes are largely (but not always; see ADCC, earlier) invisible to antibody-mediated defenses. Persons with defects in antibody formation are at greatest risk for infection with encapsulated bacteria such as pneumococci.

CELLULAR DEFENSES AGAINST INFECTION Phagocytic Cells Phagocytic cells—neutrophils and macrophages—are rapidly recruited to sites of microbial invasion by chemo attractant cytokines called chemokines, among other mechanisms. These cells are able to ingest (phagocytose) microbes directly and, even more efficiently, when the microbes are opsonized (coated with antibody or complement), through attachment to specific receptors on the phagocyte cell surface. Once ingested, microbes are killed by a system of enzymes and other antimicrobial systems. These cells are efficient mediators of defense against many bacteria and fungi; decreases in the numbers or function of neutrophils place persons at risk for bacterial and fungal infection. Macrophages also serve as “professional antigen-presenting cells” (see later) and can activate cell-mediated immune defenses by presenting digested microbial peptides to T cells.

T Lymphocytes T lymphocytes are critical effector and helper cells of the adaptive cell-mediated immune response that are generated through a complex process of selection in the thymus gland. In the thymus, the genes encoding the T-cell antigen receptor are rearranged, generating an enormous diversity of T-cell receptor (TCR) structures. T cells recognize peptide antigen bound by host cell surface human leukocyte antigens (HLAs). T cells with insufficient affinity or too great an affinity for host HLAs fail to survive thymic development. Thus the population of T cells with intermediate affinity for host HLA molecules that survive thymic maturation maintains a diverse yet selected repertoire of TCRs capable of recognizing a wide array of peptides when bound by cell surface HLA

Chapter 92—Host Defenses Against Infection molecules. The TCR of CD4+ T cells recognizes ingested peptides bound by class II HLA molecules, whereas class I HLA molecules bind peptides typically synthesized within the cell by invading pathogens for recognition by the TCRs of CD8+ T cells. Not surprisingly, therefore, after TCR engagement, CD8+ T cells destroy infected cells expressing the foreign peptides, whereas CD4+ T cells are activated largely to express T-helper cytokines that enhance the function of other immune cells such as CD8+ T cells, natural killer (NK) cells, macrophages, and B lymphocytes. On encountering antigen for the first time in lymph nodes, naive CD4+ T cells proliferate and differentiate into effector cells with one of several functional phenotypes: TH1 CD4+ T cells produce predominantly interleukin (IL)-2 and interferon (IFN)-γ, tend to activate macrophages and induce B cells to produce opsonizing antibodies, and are central to an effective cellular immune response. TH2 cells, on the other hand, produce mainly IL-4, IL-10, and IL-13, activate mast cells, induce IgM, IgE, and IgA production by B cells, and shift the system toward the humoral immune response. The balance between these two profiles is particularly important in infections caused by certain intracellular organisms, which require a vigorous TH1 response to be eliminated, among other aspects of the immune response. A third functional phenotype is that of the T regulatory cell (Treg). T regulatory cells express high levels of the IL-2 receptor CD25 and the forkhead box transcription factor P3 (FOXP3) and typically serve to modulate immune responsiveness. A third differentiation subset of CD4+ T cells, termed TH17 because of its preferential expression of proinflammatory molecules of the IL-17 family (as well as IL-22), has recently been described and is important in protection against extracellular bacteria and fungi. Selective depletion of TH17 cells in the intestinal mucosa may also play a role in the pathogenesis of progressive HIV-related immunodeficiency through interference with the epithelial barrier function against microorganisms in the intestinal lumen. Destruction of target cells by cytolytic CD8+ T cells can be mediated by receptor-ligand interaction, whereby binding of receptors on the target cell (such as Fas) by ligand on the effector cell results in activation of programmed cell death (apoptosis) of the target. Perhaps more important, cytolytic cells are enriched for perforin, which, like the terminal components of complement, produces pores in the target cell membrane, and granzymes that gain entry to target cells through these pores and induce programmed cell death of the target. Impairments in T-cell numbers or function place persons at particular risk for infection with pathogens that replicate within host cells. Because of their central role in mediating immunologic help, decreases in CD4+ T cells or their function also diminish many other aspects of host defense, such as antibody responses.

Natural Killer Cells NK cells are large granular lymphocytes that, like CD8+ T cells, have cytolytic function. These cells can kill tumor cells or normal cells infected by viruses. They are most active against target cells with low-level expression of class I HLA molecules, which, when present, activate inhibitory molecules on the NK cell surface. Because many viruses decrease host HLA class I expression as a means to evade host cytotoxic T-lymphocyte recognition, it is thought that NK cells

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may serve to identify and lyse cells resistant to antigenspecific T-cell–mediated cytotoxicity. As an effector of innate or nonadaptive host defense, NK cells are thought to be important also in early responses to viral infections and in defense against malignancy. NK cells also have receptors for IgG that, when binding the NK cells to target cells expressing viral antigens on the surface, can activate target cell lysis by the NK cell (ADCC). Rarely, persons with dramatic decreases in numbers of NK cells have been found to experience repeated and severe herpesvirus infections.

How Cells Communicate with Other Cells Cellular interactions are critical for host defense against microbes. Cells need to signal other cells in order to attract them to sites of infection; cells can also arm and activate other cells to perform their function more effectively, and cellular interactions are essential to generate and amplify host adaptive immune responses. Cells establish these communications in two basic ways: by direct contact and by the expression of soluble factors—cytokines that bind to cellular receptors and result in the generation of intracellular signals that affect the function of the cell. Some cytokine receptors are very specific for a single cytokine (e.g., the high-affinity IL-2 receptor and IL-2), whereas others can be triggered by multiple cytokines (as is often the case for chemokine receptors). Chemokines are cytokines that induce cellular movement and play important roles in trafficking cells to appropriate sites. Different cell types may express the same cytokine, and one cytokine may target several cell types, resulting in different effects in each. Thus the network of cellular interactions in host defense can be quite complex.

INTERFERONS IFNs are antiviral cytokines that can be induced as a response to viral infection; these cytokines also have potent effects on host defense cells and the priming of adaptive immune defenses. Type I IFNs (α and β) are produced by virusinfected cells, whereas type II IFN (IFN-γ) is produced by T cells and NK cells. The type I IFNs are induced by a variety of stimuli including double-stranded RNA that is not present in uninfected cells; therefore immediately after viral infection takes place, IFN is expressed by the infected cell and acts on IFN receptors to activate a number of host antiviral mechanisms, thereby rapidly attenuating viral replication. Hundreds of host genes can also be activated by type I IFNs, and thus IFNs not only activate antiviral defenses but also induce a complex array of cellular genes that prime and activate host defenses. IFN-γ also activates cytolytic activity of T cells and NK cells and activates monocytes.

How Enormous Diversity in Immune Recognition Is Possible Because there is enormous diversity in the structure and sequence of microbial pathogens, host defenses must have

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VH

CH1


VL

VL

CL

CL

VH Fab (binds antigen) CH1

Hinges

CH2

Cut

CH2 Fc (mediates activity)

CH3

CH3

Disulifide bonds V – variable L – light chain C – constant C – heavy chain

Parts of variable regions are hypervariable

Figure 92-2 Diagram of the overall structure of immunoglobulin G, which is the basic structural pattern for all immunoglobulins (see text), drawn to highlight the various reactive areas and to emphasize the globular domain features of the immunoglobulin molecule. (From Bennett JC: Approach to the patient with immune diseases. In Bennett JC, Plum F [eds]: Cecil Textbook of Medicine, 20th ed. Philadelphia, WB Saunders, 1996, p 1394.)

the ability to generate and maintain a diverse repertoire of defenses against potential invaders. Both the humoral (B-cell driven) and cellular (T-cell driven) arms of the adaptive immune response are activated by the specific interaction of foreign antigen with cellular receptors. In the case of B cells, the receptor is a surface Ig (antibody) molecule that recognizes three-dimensional structures; in the case of the T cells, the receptor recognizes short foreign peptides from 8 to 20 amino acids in length that are bound to host HLA molecules. It is the flexibility of T-cell and B-cell receptor rearrangements that permits the adaptive immune system to respond to a large number of antigenic structures. B cells and T cells appear to use similar mechanisms to generate and express the diversity required for such a broad range of specific antigenic responses. Five classes of antibodies (isotypes) are recognized (see Table 92-1). An IgG antibody (Fig. 92-2) consists of two light (κ or λ) chains and two heavy chains. Each antibody has constant regions, which are identical in structure to all antibodies of that class, and distinctive antigen recognition sites whose structures are variable. An IgG1 molecule has two such antigen-combining sites. The antigen-combining sites of antibody molecules recognize the three-dimensional structure of an antigen and bind to it in a lock-and-key manner through multiple weak, noncovalent interactions. The variable regions consist of the approximately 110 amino-terminal amino acids of each chain. Three short, hypervariable regions are present in each of the light and heavy chains. The six hypervariable regions form the antigen-combining site. Antibody diversity is generated as B lymphocytes mature and is understood at the molecular level. The variable portion of the heavy chain is encoded by three different genes: V, D, and J; investigators have identified 500 to 1000 different V genes, 10 D genes, and 4 J genes. The variable

portions of the light chains are encoded by V and J genes; investigators have identified 200 possible V genes and 6 J genes. During the differentiation of B cells in the bone marrow, somatic translocations randomly select the V, D, and J heavy chain genes and the V and J light chain genes that will be transcribed in that cell. The diversity achieved by this means is enormous. Somatic mutations in B cells as they divide after encountering antigen in lymphoid tissue (see later) allow the possibility of improving the fit between antibody and antigen; repeated or sustained exposure to antigen selects B cells capable of producing antibody with the highest binding affinity. These circulate as memory cells. T lymphocytes can be divided into two subpopulations based on the polypeptide chains constituting the antigen receptor. The αβ T cells, constituting the larger population (approximately 95%), possess a receptor consisting of a heterodimer of α and β polypeptide chains. The variable portion of the αβ TCR is composed of the approximately 100 aminoterminal amino acids. The generation of diversity is by translocation of V, D, and J genes; this takes place as the cells mature within the thymus. During thymic maturation, T cells are selected for survival and exportation into the periphery according to their affinity for self-HLA molecules. Those with too great an affinity for self-peptides and HLA molecules and those with too low an affinity for self-HLA do not survive. Thus T cells that may have “autoimmune” reactivity and those with affinities too low to recognize any peptide bound to host HLA molecules are largely deleted from the circulating T-cell pool. The TCR is directed at the foreign peptides bound by cell surface HLA molecules. αβ T cells can be divided by their surface expression of glycoproteins into CD4 and CD8 subpopulations. CD4 and CD8 cells also differ in their genetic restriction and function. Peptides bound by class I HLA are recognized by CD8+ T cells, whereas peptides bound by HLA class II molecules are recognized by CD4+ helper T cells. The TCR recognizes linear peptides of 8 to 20 amino acids in length. Importantly, in addition to their crucial role in recognizing antigens presented in this manner, T cells also provide costimulatory signals that enable the maturation and proliferation of naive B cells as they encounter antigen (discussed earlier), and thus link the humoral and cellular immune response (see discussion of the antibody response, later). Another subpopulation of T lymphocytes, γδ T cells, constitutes fewer than 5% of circulating and lymphoid T cells. These cells do not express CD4 or CD8; their TCRs contain heterodimers of γ and δ chains. Although there is diversity in the rearrangement of these chains, it is far less than that seen among αβ T cells. γδ T cells may not respond to peptides bound to major HLA molecules but instead tend to be activated directly by phospholipid antigens, by heat shock proteins, and by minor HLA molecules. Thus these cells comprise a defense intermediate between the intrinsic and adaptive host defenses.

Host-Microbe Interaction THE PRIMARY ENCOUNTER AND ROLE OF INNATE DEFENSES The skin and mucosal surfaces represent the primary interface with the external world and microbes. At these sites,

Chapter 92—Host Defenses Against Infection anatomic barriers that also include certain intrinsic defenses and the normal microbial colonists as well as secretory antibody help to defend against the development of invasive disease. Mucosal colonization by pathogenic microbes, such as pneumococcal colonization of the oropharynx, can induce an adaptive immune response. If this response develops before tissue invasion takes place, colonization may result in acquisition of a protective antibody response. However, factors that disrupt normal host defenses, such as a depressed sensorium blocking gag and cough reflexes, cigarette smoking suppressing ciliary clearance, or intercurrent influenza virus infection denuding the tracheal epithelium, can increase the likelihood that colonization with a pathogenic microbe will result in invasive infection. Once anatomic barriers are breached and an invading microbe gains access to tissues, other intrinsic host defenses come into play rapidly. These rapid responders are phagocytic cells that express “toll-like” receptors for microbial elements such as cell wall lipopolysaccharide, other cell wall products, flagellins, or microbial nucleotide sequences. Phagocytic cells are then activated to ingest nearby microbes and to induce expression of chemotactic cytokines that facilitate entry of additional inflammatory cells to the site of microbial breach. Some microbes are armed to resist these defenses, as is the case for bacteria with capsules that resist phagocytosis. Host complement can be activated to bind to these capsules, helping to opsonize the bacterium to enhance phagocytosis and also to enhance ingress of inflammatory cells to the site. Because it generally takes several days to a few weeks for the adaptive immune system to mobilize and generate sufficient effector activity to protect the host, one key role of the innate immune system is to provide a method of limiting microbial replication and pathogenesis until the more potent and specific adaptive immune response can be mobilized. Activation of microbicidal phagocytic cells, complement and NK cell activation, and induction of antiviral IFNs all may play a role in the early innate defense against microbial invasion. It should be emphasized, however, that there are many collaborative interactions between innate and adaptive defense mechanisms to ensure optimal arming of host defenses.

GENERATION OF ADAPTIVE IMMUNE RESPONSES Cell-Mediated (T-Cell) Responses Skin and mucosal tissue contain large numbers of dendritic cells, such as Langerhans cells, that also express toll-like receptors. These cells ingest foreign antigens and foreign microbes and also may ingest dying inflammatory cells that have themselves ingested invading microbes. As they migrate to lymphoid tissues, these dendritic cells mature, degrading the ingested antigens and expressing these microbial peptides on cell surface HLA molecules. At the same time, these cells lose the ability to ingest additional material and begin to express numerous co-receptors that enhance their ability to interact with and activate T lymphocytes. In lymphoid tissues, these professional antigen-presenting cells encounter “naive” T cells that have undergone TCR gene rearrangement in the thymus, and a small number of these cells will (by chance) express a TCR configuration that recognizes an HLA-bound peptide. What largely restricts the breadth of immune recognition is the ability of peptide to bind to that

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T cell Extracellular CD8 for HLA I CD4 for HLA II

T-cell receptor CD3 LFA-1 CTLA-4 CD28

HLA Peptide Antigen-presenting cell ICAM-1

CD80/86

Figure 92-3 The molecular events in antigen presentation. Peptides within human leukocyte antigen (HLA) molecules on the antigen-presenting cell (APC) are bound weakly by T-cell receptor α and β chains. This interaction is stabilized and facilitated by interactions between the adhesion molecules LFA-1 on the T cell and its ligand ICAM-1 on the APC. T-cell and APC interactions between costimulatory molecules CD80 and CD86 on the APC and receptors such as CD28 or CTLA-4 on the T cell can result in T-cell activation or suppression, respectively.

particular HLA molecule. Thus different HLA molecules can bind different peptides, and this variable binding ability (and not so much the recognition by the T cell) determines an individual’s ability to recognize a foreign peptide and mount an immune response to it. As discussed earlier, T cells with high affinity for self-peptides or too low an affinity for self-HLA molecules have already been deleted within the thymus. The relatively low-affinity interactions between TCR and HLA-bound peptide are supported by multiple co-receptor–ligand and adhesion molecule interactions between the T cell and antigen-presenting cell that also result in activation of the T cell (Fig. 92-3). The naive T cell is thus activated to divide time and time again, rapidly expanding the number of T cells with the same clonal antigenic specificity. T cells thus activated are no longer antigen “naive” but are now activated to express cytokines and/or to have cytolytic activity, and some will develop long-lived “memory” function. Cytokines expressed by CD4+ T-helper cells enhance the activity of other immune cells such as cytolytic CD8+ T cells and NK cells and are also critical to the development and maturation of B lymphocytes to result in the generation of antibody responses. T-helper cells also interact directly with dendritic cells, affecting their maturation and function.

Antibody Response In lymphoid tissues, more complex antigens, including whole microbes, can be bound in an antigen-specific fashion by B lymphocytes, which have as their antigen receptor membrane-bound immunoglobulins (IgD and IgM). Thus bound, a particle can be ingested by the B cell and degraded, and then these microbial peptides are expressed on the B-cell surface HLA class II molecules. Thus, B lymphocytes may serve as professional antigen-presenting cells for recognition by CD4+ T cells. For most antigens, therefore, attraction of CD4+ T-cell help is essential to permit B lymphocyte expansion and ultimately antibody synthesis. As is the case for the interaction between the CD4+ T cell and other professional

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antigen-presenting cells, multiple receptor-ligand interactions stabilize the interaction between the TCR and the peptide HLA molecule that it recognizes on the B-cell surface. At the site of this intimate interaction, the CD4+ T cell is activated to express T-helper cytokines that in turn activate the B cell, promoting cellular division and maturation. In this fashion microbial peptides that are recognized by CD4+ T cells induce the “help” that is needed to result in generation and amplification of an antibody response to that microbe. Recognition of this basic principle has resulted in the development of “conjugate vaccines” that, through linkage of immune help inducing peptides to microbial sugars (which themselves do not induce T-cell responses) can enhance the antibody responses to these sugars. Conjugate vaccines are now used to prevent Haemophilus and pneumococcal infection. The B lymphocytes thus activated by binding antigen to their surface receptors and helped by their interaction with CD4+ T cells begin clonal replication and maturation. Replication amplifies the “mass” of antigen-reactive B cells, and maturation involves both transformation of B cells into antibody-secreting plasma cells and the induction of “classswitching,” wherein the variable antigen-binding domains of the antibody are “switched” by gene rearrangements onto constant domains of different classes of antibody molecules. Thus an initial IgM response is followed later by an IgG response with the same specificity in terms of antigen recognition (hence the utility of a high-level IgM response to a microbial antigen as a clinically meaningful indicator of recent infection). These events take place largely in germinal centers within lymphoid tissue that is enriched also with follicular dendritic cells. These follicular dendritic cells can, for periods of years, trap and hold intact antigens on their surfaces and facilitate B-lymphocyte maturation. During the early course of antibody generation, the affinity of antibody molecules for their antigens can increase. This affinity maturation takes place during the rapid expansion of B lymphocytes and is the consequence of somatic hypermutation of sequences within the hypervariable regions of the antibody genes. Progeny B lymphocytes with greater surface immunoglobulin (receptor) affinity for antigen will be more rapidly activated to divide and will “outcompete” B lymphocytes with lower affinity receptors. The antibodies thereby secreted by progeny plasma cells become increasingly capable of binding microbial antigens with higher affinity. Thus the humoral immune response “evolves” in real time, selecting for B cells producing antibodies with progressively higher affinity for microbial pathogens.

Microbial Pathogenesis versus Host Defenses— the Continuing Drama RESISTANCE TO EXTRACELLULAR BACTERIA: ENCAPSULATED ORGANISMS Streptococcus pneumoniae The type-specific polysaccharide capsule is a major virulence factor because of its antiphagocytic properties. Antibody to the polysaccharide is itself capable of preventing pneumo-

coccal disease, as reflected by experimental studies and the efficacy of pneumococcal polysaccharide vaccines. In the absence of immunity, pneumococci reaching the alveoli are not effectively contained by the host. Their phagocytosis by neutrophils is inefficient, because organisms must be trapped against a surface to be ingested (surface phagocytosis). The pneumococcus does, however, elicit a neutrophilic inflammatory response. The organism activates complement by the alternative pathway and interactions of C-reactive protein in serum with pneumococcal Cpolysaccharide. Activated complement fragments (C3a, C5a, and C567) are chemotactic for neutrophils. Opsonic complement fragments (C3b) coating pneumococci favor their attachment to neutrophils but are less effective in promoting phagocytosis and killing than is specific antibody. Clinical observations also directly support the primal role of antibody in immunity. The development of specific antibody on days 5 to 9 of untreated pneumococcal pneumonia may produce a clinical “crisis,” with dramatic resolution of symptoms. Opsonization of S. pneumoniae by type-specific antipolysaccharide antibody promotes ingestion and oxidative burst activity, with destruction of the organism.

Neisseria meningitidis Capsular polysaccharide also represents an important virulence factor for meningococci. In addition, pathogenic Neisseria species produce an IgA protease that dissociates the Fc fragment from the Fab portion of secretory and serum IgA and thus interferes with effector properties of the antibody molecule. Antibody-dependent, complementmediated bacterial killing is the most critical host defense against meningococci. Therefore the presence of bactericidal antibody is associated with protection against the meningococcus. In epidemic situations, 40% of persons who become colonized with the epidemic strain but who lack bactericidal antibodies develop disease. Protective serum antibody is elicited by colonization with the following: (1) nonencapsulated and encapsulated strains of meningococci of low virulence, which elicit antibodies cross-reactive with virulent strains, and (2) Escherichia coli and Bacillus species with cross-reacting capsular polysaccharides. The lack of bactericidal activity in the serum of adolescents and adults manifesting susceptibility to N. meningitidis may be a result of blocking IgA antibody. Susceptibility of patients lacking C6, C7, or C8 to meningococcal infection provides important evidence that the dominant protective mechanism against this organism involves complement-mediated bacteriolysis.

RESISTANCE TO FACULTATIVE INTRACELLULAR PARASITES: MYCOBACTERIUM TUBERCULOSIS Activation of host phagocytes provides the critical defense mechanism against M. tuberculosis. Primary infection progresses locally in the nonhypersensitive host, because ingested organisms persist and multiply within mononuclear phagocytes. The bacteria escape intracellular digestion by secreting products that inhibit phagolysosomal fusion. Antibody-coated mycobacteria do not evade phagolysosomal fusion but nonetheless resist degradation, probably because of shielding provided by their rich lipid content. The development of cellular immunity leads to T-

Chapter 92—Host Defenses Against Infection lymphocyte–dependent macrophage activation and to the killing of the intracellular tubercle bacillus organism. The lesions of primary tuberculosis regress. However, latent foci persist, and delayed reactivation remains a threat throughout the lifetime of the host.

RESISTANCE TO OBLIGATE INTRACELLULAR PARASITES: VIRUSES Host antiviral defense is characterized by overlap and redundancy, which allow an effective response to most viral agents. The key element of the response varies with the virus, the site, and the timing. Initially, infection is limited at the local site by type I IFNs, which increase the resistance of neighboring cells to spread of the infection. Complement directly neutralizes some enveloped viruses. NK cells destroy infected cells, a process enhanced by IFNs. As specific antibody is produced, IgA may neutralize the virus at mucosal surfaces; IgG may neutralize virus that has spread systemically to extracellular sites and also may allow uptake and destruction by FcR-bearing effector cells. Later, effector cytotoxic T

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lymphocytes are expanded and activated to lyse host cells expressing viral peptides in the context of HLA antigens. The host thus directs several defenses against viral infection. Humoral defenses are active against extracellular viruses and, if neutralizing antibody is present at high enough levels before infection, may prevent clinical infection entirely. Cell-mediated defenses largely play more critical roles in attenuating the magnitude of viral replication during chronic infection. Viruses at the same time have evolved numerous mechanisms to blunt or block host antiviral defenses. Many viruses can decrease the expression of class I HLA molecules on cells they infect, thereby limiting recognition of these cells by CD8+ cytotoxic T lymphocytes. Many viruses that cause chronic infection, such as herpesviruses and HIV, can maintain a latent infection whereby, in the absence of viral protein synthesis, there are no viral peptide targets for recognition by cytotoxic T lymphocytes. Other viruses have acquired gene sequences that encode homologues of host cytokine or cytokine receptor genes that may help viruses escape from host immune surveillance or contribute to viral pathogenesis.

Prospectus for the Future • Increased understanding of the molecular and cellular mechanisms responsible for the establishment and regulation of the immune response • More accurate and reproducible techniques to quantify and evaluate the different components of the immune response • Expanding role of genomics and proteomics as techniques to map the biochemical profiles that characterize the

References Autran B, Molet L, Lederman MM: Host defenses against viral infection. In Boucher CAB, Galasso GJ (eds): Practical Guidelines in Antiviral Therapy. Amsterdam, Elsevier, 2002, pp 65-94. Delves PJ, Roitt IM: The immune system (I). N Engl J Med 343:37-49, 108-117, 2000. Goronzy JJ, Weyand CM: The innate and adaptive immune systems. In Goldman L, Ausiello D (eds): Cecil Textbook of Medicine, 22nd ed. Philadelphia, Elsevier, 2004, pp 208-217. Holland SM, Gallin JI: Evaluation of the patient with suspected immunodeficiency. In Mandel GL, Bennett JE, Dolin R (eds): Principles and Practices of Infectious Diseases, 6th ed. Philadelphia, Elsevier, 2005, pp 149-160.

immune response to various pathogens, as well as prevalent antigens • Innovative therapeutic interventions aimed at modulating specific components of the immune response selectively, and increased interest in clinically meaningful ways to evaluate the effectiveness of those interventions

Janeway CA, Travers P, Walport M, Shlomchik M: Immunobiology: The Immune System in Health and Disease, 5th ed. New York, Garland Publishing, 2001. Karp DR, Holer VM: Complement in health and disease. In Goldman L, Ausiello D (eds): Cecil Textbook of Medicine, 22nd ed. Philadelphia, Elsevier, 2004, pp 233-240. Schwartz RS: Shattuck Lecture—Diversity of the immune repertoire and immunoregulation. N Engl J Med 348:1017-1026, 2003. Von Andrian UH, Mackay CR: T-cell function and migration. Two sides of the same coin. N Engl J Med 334:1020-1034, 2000.

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93

Laboratory Diagnosis of Infectious Diseases Benigno Rodríguez and Michael M. Lederman

F

ive basic laboratory techniques can be used in the diagnosis of infectious diseases: (1) direct visualization of the organism, (2) detection of microbial antigen, (3) a search for “clues” produced by the host response to specific microorganisms, (4) detection of specific microbial nucleotide sequences, and (5) isolation of the organism in culture or propagation in cell culture. Each technique has its use and its pitfalls. The laboratory can usually provide the clinician with prompt, accurate, and, if the techniques are used judiciously, inexpensive diagnosis.

can identify Treponema pallidum, and electron microscopy can sometimes detect viral particles in infected cells.

INDIA INK PREPARATION A drop of centrifuged CSF is placed on a microscope slide next to a drop of artist’s India ink. A coverslip is placed over the drops, and the area of mixing of CSF and India ink is examined at 100× magnification. Cryptococci are identified by their large capsules, which exclude the India ink (see Fig. 93-1).

Diagnosis by Direct Visualization of the Organism

Diagnosis by Detection of Microbial Antigens

In many infectious diseases, pathogenic organisms can be directly visualized by microscopic examination of readily available tissue fluids. With the use of Gram or acid-fast stains, bacteria, mycobacteria, and Candida can be readily identified. An India ink preparation can often identify Cryptococcus, and potassium hydroxide (KOH) preparations can occasionally identify other fungal pathogens. Although antigen detection techniques are rapidly supplanting conventional staining and microscopy for identification of organisms such as Giardia in stool samples and Cryptococcus in cerebrospinal fluid (CSF) specimens (see later) because of their greater sensitivity and their decreased susceptibility to interobserver variation, the expediency of traditional direct visualization techniques in the presence of a large organism burden remains unmatched by these approaches. Examples of positive specimens prepared by conventional staining techniques are shown in Figures 93-1 and 93-2. Other techniques can also reveal clinically relevant pathogens. Silver staining using the Gomori methenamine technique can identify most fungi, including Pneumocystis jirovecii. Experienced pathologists can also identify P. jirovecii on Giemsastained specimens of induced sputum. Darkfield microscopy

Certain pathogens can be detected by examination of specimens for microbial antigens (Table 93-1). These studies can be performed rapidly—often within 1 hour. The diagnosis of meningitis caused by Streptococcus pneumoniae, Cryptococcus neoformans, some strains of Haemophilus influenzae, and Neisseria meningitidis can be made rapidly by detection of specific polysaccharide antigen in the CSF. Although these diagnoses may also be made by Gram stain or India ink preparation, antigen detection is especially helpful when attempts at direct visualization of the pathogen are not diagnostic (e.g., in the patient with partially treated bacterial meningitis). Immunofluorescence techniques (Fig. 93-3) using antibodies directed against the organisms identify pathogens such as Legionella pneumophila and Bordetella pertussis in respiratory secretions. Immunofluorescence can also be used to identify cells infected with influenza virus, respiratory syncytial virus, and adenovirus. Detection of urinary pneumococcal antigen can enhance the diagnostic capabilities of direct visualization and culture techniques in community-acquired pneumonia. Quantitation of cytomegalovirus (CMV) antigen in blood may help predict the development of active disease in immunocompromised patients.

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Chapter 93—Laboratory Diagnosis of Infectious Diseases The demonstration of hepatitis B surface antigen in blood establishes the presence of infection by this virus.

Diagnosis by Examination of Host Immune or Inflammatory Responses Histopathologic examination of sampled or excised tissue often shows patterns of the host inflammatory response that

Figure 93-1 India ink preparation of cerebrospinal fluid revealing encapsulated cryptococci. Note the large capsules surrounding the smaller organisms.

Figure 93-2 Tzanck preparation for diagnosis of herpesvirus infection. Note the multicolored giant cell (bottom) characteristic of herpes infection.

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can narrow down diagnostic possibilities. As a general rule, a polymorphonuclear leukocytic infiltrate suggests an acute bacterial process. A lymphocytic infiltrate suggests a more chronic process and is characteristically seen in viral, mycobacterial, and fungal infections. Similarly, examination of infected fluids such as CSF may provide clues to possible causes. Bacterial infections generally provoke a polymorphonuclear leukocytosis with elevated protein and depressed glucose concentrations. Viral infections most often provoke a lymphocytic pleocytosis; protein elevations are less marked, and glucose levels are usually normal. Eosinophilia suggests helminthic infestations or certain fungal infections, such as coccidioidomycosis or aspergillosis, particularly the allergic forms of the latter. Granuloma formation suggests a mycobacterial cause. Certain parasites (such as Schistosoma species) and fungi (such as Histoplasma, Cryptococcus, and Blastomyces can also lead to granuloma formation. Some diseases, such as syphilis (obliterative endarteritis), catscratch disease (mixed granulomatous, suppurative, and lymphoid hyperplastic changes), and lymphogranuloma venereum (stellate abscesses), have fairly characteristic histologic features. Several viral infections produce characteristic changes in host cells, which are detectable by cytologic examination. Skin or respiratory infection with herpesviruses, or pneu monia caused by CMV or measles virus, for example, can be diagnosed with reasonable accuracy by cytologic examination (e.g., Tzanck preparation for herpesvirus infection). Host cell–mediated immune responses can be used to help make certain diagnoses. A positive skin test for delayedtype hypersensitivity to mycobacterial or fungal antigens indicates active or previous infection with these agents. A negative skin test may be seen despite active infection in individuals with depression of cell-mediated immunity (anergy). Control skin tests using commonly encountered antigens (e.g., Candida, mumps, Trichophyton) have been used in an attempt to exclude global anergy as the reason for a negative skin reaction, but their value as a diagnostic tool is questionable and they are therefore not routinely recommended. The QuantiFERON-TB test is an assay for detection of interferon-γ production by Mycobacterium tuberculosis–specific lymphocytes, and is an example of a clinically useful in vitro diagnostic procedure based on detection of the cellular immune response to a specific pathogen. Host humoral responses may be used to diagnose certain infections, particularly those caused by organisms whose cultivation is difficult (e.g., Ehrlichia chaffeensis) or hazardous to laboratory personnel (e.g., Francisella tularensis). In general, two sera are obtained at intervals of at least 2

Table 93-1 Diseases Often Diagnosed by Detection of Microbial Antigens Disease

Assay

Agent Detected

Meningitis

Latex agglutination

Respiratory tract infection

Immunofluorescence Enzyme immunoassay Enzyme immunoassay Radioimmunoassay

Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitides, Cryptococcus Bordetella pertussis, Legionella pneumophila, influenza virus, respiratory syncytial virus, adenovirus Chlamydia species, herpes simplex viruses 1 and 2 Hepatitis B surface antigen

Genitourinary tract infection Hepatitis B

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Assays That Detect Microbial Nucleotide Sequences Detection of microbial nucleotide sequences can provide a sensitive and specific means of identification of pathogens in clinical specimens. These genetic molecular diagnostic techniques can provide rapid speciation of slow-growing microbial isolates. In addition, these techniques can also provide rapid quantitation of pathogens that can establish the prognosis and also determine the effectiveness of modes of therapy. Finally, genetic analyses can identify genetic markers of antimicrobial resistance that can guide the selection of therapy. The exquisite sensitivity and specificity of these techniques are consequences of the specificity of DNA base pairing and the dramatic amplifications of signals that can be provided by techniques such as the quantitative polym erase chain reaction (Fig. 93-4), nucleic acid sequence–based amplification, and branched-chain signal amplification analyses. The sensitivity of these techniques has revolutionized laboratory diagnostics. For example, most standard techniques for detection of microbial antigens cannot reliably detect fewer than 100,000 molecules in clinical samples. In contrast, the genetic techniques discussed earlier are being routinely used now to identify as few as 20 to 50 molecules in clinical samples and can be modified to have even greater sensitivity. Table 93-2 lists some examples of diseases in which molecular diagnostic methods have represented a major advance in recent years. Figure 93-3 Diagram of the steps in the enzyme-linked immunosorbent assay (ELISA). Shown here is the form of ELISA used to detect antibodies (such as the test used to detect HIV infection); other forms of ELISA detect antigens. The process begins by adding the specimen to a well that has a purified antigen adsorbed to its inner surface, along with irrelevant proteins to cover the remaining well surface and prevent nonspecific binding. If specific antibodies are present in the sample, they will bind to the antigen; an antibody directed against human immunoglobulin labeled with an enzyme is then added. In the final step, the substrate for the enzyme is added; if there is attached antibody in the well, the linked enzyme will interact with the substrate and produce a color change that is proportional to the amount of antibody and can be read by a spectrophotometer.

weeks, and a fourfold or greater rise (or fall) in antibody titer generally suggests a recent infection. Antibodies of the immunoglobulin M class also suggest recent infection. Depending on the organism, assays may detect either specific (hepatitis viruses) or nonspecific, cross-reactive antibodies (syphilis non-treponemal tests). From another perspective, measurement of antibody levels in serum can determine if a person is likely protected from acquisition of infection or on the other hand might be a candidate for immunization. Measurement of serum antibodies to hepatitis A and hepatitis B virus is often used to determine if persons at risk are candidates for immunization.

Clinical Applications of Molecular Diagnostics SPECIATION The slow replication of mycobacteria limits rapid speciation of these organisms after their identification in clinical samples. In certain clinical settings, such as those that may occur in persons with human immunodeficiency virus (HIV) infection, the distinction between nontuberculous mycobacteria and M. tuberculosis may be particularly important. Genetic probes that distinguish among these organisms can provide rapid speciation after only limited growth.

DIAGNOSIS OF INFECTION In acute HIV infection, detection of genomic HIV-1 RNA in plasma can provide diagnosis of this syndrome weeks before the development of diagnostic HIV specific antibodies (see Chapter 108). Nucleic acid amplification techniques are now routine for the diagnosis of gonorrhea and Chlamydia infections and can be performed on a single specimen, with a rapid turnaround time. Detection of herpes simplex virus sequences within CSF can provide a sensitive and specific diagnosis of herpes simplex encephalitis. Similar assays can be used for diagnosis of CMV, JC virus, Epstein-Barr virus, and Bartonella henselae infection. In certain anatomic

Chapter 93—Laboratory Diagnosis of Infectious Diseases 1

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3' Figure 93-4 Schematic representation of polymerase chain reaction (PCR). The reaction solution contains the sample—presumably containing the target DNA, nucleotides, and primers, which will serve as building blocks for the amplified product, and polymerase enzymes that will catalyze the attachment of the nucleotides to the growing chain. (If the viral genome is composed of RNA, the genome must be first reverse transcribed to provide a complementary DNA template.) The first step in genomic amplification is denaturation, during which the solution is heated to 95° C to separate the two strands of DNA. The temperature is then lowered to allow the primers to attach to their complementary sequences on the single DNA strands, a process known as annealing. Finally, the mixture is heated again to a temperature at which the DNA polymerase catalyzes the attachment of further nucleotides to the primers (extension) until full double-stranded duplicates of the original DNA molecules are produced. If this process is repeated multiple times in a thermal cycler, a single DNA molecule can yield one million molecules after approximately 20 cycles.

locations such as the pericardium and the central nervous system, nucleic acid amplification may help in the diagnosis of tuberculosis. It is anticipated that numerous infectious diseases will soon be diagnosed with great sensitivity by means of these techniques. The exquisite sensitivity of this technique may, however, yield false-positive results unless the assays are carefully standardized.

QUANTIFICATION OF MICROBIAL BURDEN Molecular diagnostic assays have been refined and standardized to permit reliable quantification of microbial genomic sequences in clinical samples. Quantification of CMV DNA, for example, has proven a useful tool in identifying individuals at risk for developing progressive CMV disease during chemotherapy-induced or organ transplantation–induced immunosuppression. These quantitative assays have also

provided evidence that the magnitude of microbial replication is predictive of disease progression in HIV infection, and sequential application of these techniques is now used routinely to monitor the activity of therapy for HIV and for hepatitis C virus infection.

DETECTING GENETIC MARKERS FOR ANTIMICROBIAL RESISTANCE Microbial resistance to therapeutic interventions is an increasing problem in infectious diseases. When genetic sequences that confer resistance to therapies are known, assays to detect them can be applied rapidly to clinical samples, providing information that can be used to select treatment regimens. Direct analysis of plasma HIV sequences has provided genetic information that can predict the failure of specific modes of therapy; under certain circumstances, routine application of this information to the selection of

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Table 93-2 Diseases in Which Molecular Diagnosis Techniques Are Commonly Used Pathogen

Test

Clinical Situation

Hepatitis C virus

Quantitative PCR

Cytomegalovirus

PCR Hybrid capture DNA test, CMV pp67 NASBA PCR, ligase chain reaction

Confirmation of chronic infection; monitoring of the effectiveness of therapy; documentation of sustained virologic response Diagnosis of CMV encephalitis, myelitis on CSF specimens Prediction of development of clinical disease in seropositive immunocompromised patients Diagnosis of sexually transmitted diseases on a single specimen—now the standard of care in many centers Quantification of viral burden; monitoring of response to therapy; determination of infectiousness Quantification of viral replication; monitoring of response to therapy; confirmation of diagnosis in acute infection and mother-to-child transmission Etiologic diagnosis of viral meningitis Reliable diagnosis of HSV encephalitis, a life-threatening disease

Chlamydia trachomatis, Neisseria gonorrhoeae Hepatitis B virus

PCR

HIV

PCR, branched DNA amplification, NASBA

Enteroviruses Herpes simplex virus

Real-time PCR PCR

HIV, human immunodeficiency virus; HSV, herpes simplex virus; NASBA, nucleic-acid-sequence–based amplification; PCR, polymerase chain reaction.

treatment regimens has been shown to improve the success rates of antiretroviral treatment.

Diagnosis by Isolation of the Organism in Culture Isolation of a single microbial species from an infected site is generally considered evidence that the infection is caused by this organism. However, information obtained from the culture must be interpreted according to the clinical setting. For example, cultures obtained from ordinarily contaminated sites (e.g., vagina, pharynx) may be overgrown with nonpathogenic commensals, and fastidious organisms such as Neisseria gonorrhoeae are difficult to recognize unless cultured on a medium that selects for their growth. Similarly, cultures of expectorated “sputum” may also be uninterpretable if heavily contaminated with saliva. The culture of an organism from an ordinarily sterile site is reasonable evidence for infection with that organism. Conversely, the failure to culture an organism may simply result from inadequate culture conditions (e.g., “sterile” pus from a brain abscess cultured only on aerobic media). Most brain abscesses are caused by anaerobic bacteria that do not grow under aerobic conditions. Thus, when submitting samples for culture, the physician must alert the laboratory to likely pathogens. Gram stains of specimens submitted for culture are often invaluable aids to the interpretation of culture results. A Gram stain of “sputum” will readily detect contamination by saliva if numerous squamous epithelial cells are seen. In contrast, a Gram stain revealing bacteria despite negative cultures suggests infection by fastidious organisms. The presence of an organism in high density and within neutrophils strongly suggests that the corresponding bacterial isolate is causing disease rather than colonizing the patient or contaminating the specimen. Gram staining of the initial clinical specimen may also help determine the

relative importance of different isolates when cultures show mixed flora.

VIRAL ISOLATION Because all viral pathogens that can be cultured require eukaryotic cells in which to grow, virus isolation is expensive and often laborious. Throat washings, rectal swabs, or cultures of infected sites should be transported immediately to the laboratory or, if this is not possible, placed in virus transport medium and refrigerated overnight until they can be cultured in the laboratory. Certain viruses such as HIV and CMV are often cultivated from whole blood samples. Notifying the laboratory of the suspected pathogens allows selection of the best cell lines or systems for culture. The clinician must be aware of the viruses that the hospital’s laboratory can isolate, and consideration should be given to the clinical circumstances in which the specimen was obtained to properly interpret a positive result. This is particularly true in the case of viruses that can be shed intermittently in the absence of active disease, such as the herpes simplex viruses and CMV.

ISOLATION OF RICKETTSIAE, CHLAMYDIAE, AND MYCOPLASMAS Rickettsiae are cultivated primarily in reference laboratories. Diagnosis of rickettsial illness is generally made on clinical grounds and confirmed serologically. Although chlamydiae can be propagated in cell cultures used in most hospital virology laboratories, chlamydial infection is most often diagnosed through antigen detection techniques. Mycoplasmas will grow on selective media; however, the prolonged period of incubation results in little advantage over serologic diagnosis.

BACTERIAL ISOLATION Isolation of common bacterial pathogens is achieved readily by most hospital laboratories. Specimens should be carried

Chapter 93—Laboratory Diagnosis of Infectious Diseases promptly to the laboratory. In instances in which likely isolates may be fastidious (e.g., bacterial meningitis) and immediate processing cannot be ensured, the specimen should be placed directly onto the culture medium, with careful attention to sterile techniques. Widespread availability of transport media has minimized the need for this kind of approach. Blood culture is a special case of bacterial isolation technique, for which immediate inoculation into the culture medium is required. Blood culture samples are arguably some of the most critical specimen types processed by a microbiology laboratory, and errors in their collection and processing can have major clinical consequences. Common mistakes include insufficient blood volume (30 to 40 mL total is recommended for adults), collection of multiple specimens from the same venipuncture site or intravenous catheter (making it difficult to interpret the significance of normal skin colonizers and to estimate the persistence of the bacteremia), collection after antibiotic initiation, and less than meticulous aseptic technique (resulting in contaminant growth).

Isolation of anaerobic bacteria is often critically important for clinical diagnosis. When anaerobes are suspected, the specimen, if pus or liquid, can be drawn into a syringe, the air expelled, and the syringe capped before transport to the laboratory. Otherwise, specimens must be taken immediately to the laboratory or placed in an anaerobic transport medium appropriate for survival of pathogens. Because of contamination by oral anaerobes, sputum should not be cultured anaerobically unless the sample was obtained by transtracheal or percutaneous lung aspiration.

ISOLATION OF FUNGI AND MYCOBACTERIA Specimens for fungal and mycobacterial culture must be processed and cultured by the microbiology laboratory. Although some fungi and rapidly growing mycobacteria grow readily on standard agars used for routine isolation of bacteria, others, such as M. tuberculosis and Histoplasma capsulatum, must be cultured on special media for as long as several weeks.

Prospectus for the Future • Greater use of molecular methods for diagnosis and monitoring of infectious diseases

References Gill VJ, Fedorko DP, Witebsky FG: The clinician and the microbiology laboratory. In Mandell GL, Bennett JC, Dolin R (eds): Principles and Practice of Infectious Diseases, 6th ed. Philadelphia, Elsevier, 2005, pp 203-241. Versalovic J, Lupski JR: Molecular detection and genotyping of pathogens: More accurate and rapid answers. Trends Microbiol 10:S15-S21, 2002.

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• Greater use of rapid bedside tests for the diagnosis of infectious diseases

XVII

Chapter

94

Antimicrobial Therapy Benigno Rodríguez and Michael M. Lederman

O

ne of the most dramatic advances in medical practice in the twentieth century was the development of antimicrobial therapy. Antimicrobials are agents that interfere with microbial metabolism, resulting in inhibition of growth or death of bacteria, viruses, fungi, protozoa, or helminths. Some, like penicillin, are natural products of other microbes. Others, such as sulfa drugs, are chemical agents synthesized in the laboratory. Still others are semisynthetic, with chemical modifications of naturally occurring substances that result in enhanced activity (e.g., nafcillin) and/or diminished toxic effects. The most effective antimicrobials are characterized by their relatively selective activity against microbes. Some, such as penicillins and amphotericin B, interfere with the synthesis of microbial cell walls that are absent in human cells. Others, such as trimethoprim and sulfa drugs, inhibit obligate microbial synthesis of essential nucleic acid intermediates, pathways not required by human cells. Still others, such as acyclovir, an antiviral agent, are relatively inactive until metabolized by pathogen-derived enzymes. Antiretroviral agents selectively inhibit viral elements that are essential for replication. More recently antiretroviral agents have been developed that inhibit host cellular factors necessary for viral replication. Antimicrobial agents, although typically selective in activity against microbes, have variable degrees of toxicity for human cells. Thus, monitoring for toxicity during antimicrobial therapy is always important.

Pathogen If the pathogen has been clearly identified (see Chapter 93), a drug with a narrow spectrum of activity (i.e., highly selective for the particular pathogen) is usually the most reasonable choice. If the pathogen responsible for the patient’s illness has not been identified, then the physician must choose a drug or combination of drugs active against the most likely pathogens in the specific setting. In either instance, the physician must be guided by patterns of antimicrobial resistance common in the community and in the 904

specific hospital. Some pathogens (e.g., group A streptococci) are almost always sensitive to narrow-spectrum antimicrobials such as penicillin. Other pathogens, such as staphylococci, are variably resistant to penicillins but almost always susceptible to vancomycin. Resistance patterns, particularly among hospital-acquired bacteria, may vary widely and are important in devising antimicrobial strategies. Broad-spectrum antimicrobial coverage for all febrile patients (“shotgunning”) must not be substituted for carefully evaluating the clinical problem and pinpointing therapy directed toward the most likely pathogen or pathogens. Widespread use of broad-spectrum antimicrobials almost invariably leads to emergence of resistant strains or the emergence of potentially fatal pathogens such as Clostridium difficile. However, the greater the severity of a patient’s illness and the less certain the physician is of the responsible pathogen, the more important initial, empirical, broadspectrum coverage becomes. Initial empirical treatment is also frequently indicated in the immunocompromised febrile patient (e.g., the patient with severe neutropenia secondary to chemotherapy). Once the pathogen is isolated and its antimicrobial sensitivities are known, empirical therapy must be scaled down to a definitive regimen with optimal activity against the specific microorganism.

Site of Infection The location of the infection is also important in determining the selection and dosage of an antimicrobial. Deepseated infections and bacteremic infections generally require higher doses of antimicrobials than, for example, superficial infections of the skin, upper respiratory tract, or lower urinary tract. Penetration of antimicrobials into sites such as the meninges, eye, and prostate is quite variable. Therefore treatment of infections at these sites involves selection of an antimicrobial agent that penetrates these tissues in concentrations sufficient to inhibit or kill the pathogen. The meninges are relatively resistant to penetration by most antimicrobials; inflammation renders them somewhat more

Chapter 94—Antimicrobial Therapy permeable. High doses of antibiotics are therefore the rule when meningitis is treated. Bacterial infections of certain sites such as the heart valves or meninges must be treated with antibiotics that kill the microbe (bactericidal) as opposed to simply inhibiting growth (bacteriostatic). This is so because local host defenses at these sites are inadequate to rid the host of infecting organisms. Infections involving foreign bodies may be impossible to eradicate without removal of the foreign material. Antimicrobials alone are often insufficient in the treatment of large abscesses. Although many drugs achieve reasonable concentrations in abscess walls, the low pH antagonizes the activity of some drugs (e.g., aminoglycosides), and some drugs bind to and are inactivated by the high concentrations of protein, white blood cells, and their products in these collections. The large number of organisms, their depressed metabolism in this unfavorable milieu, and the frequent polymicrobial nature of certain abscesses increase the likelihood that some organisms present may be resistant to antimicrobial therapy. Therefore most abscesses should be drained whenever anatomically possible.

Characteristics of the Antimicrobial The physician must know the pharmacokinetics of the drug (i.e., its absorption, its penetration into various sites, and its metabolism and excretion) and its toxic effects, as well as its spectrum of antimicrobial activity, before selecting it for use (Table 94-1).

905

aminoglycosides and certain azalide and macrolide antibiotics, agents inhibiting protein synthesis at ribosomal sites are generally bacteriostatic.

TOXIC EFFECTS OF THE DRUG The physician must have a thorough understanding of the contraindications for use of the drug, as well as the major toxic effects and their general frequencies. This will help in evaluating the risks of treatment and will also assist in advising the patient about possible adverse reactions. History of drug hypersensitivity must be sought before any antimicrobial is prescribed. The presence or absence of previous reactions to penicillin should be documented for every patient. Patients with a history suggestive of immediate hypersensitivity to penicillin, such as hives, wheezing, hypotension, laryngospasm, or angioedema at any site, must be considered at risk for anaphylaxis. These patients should not receive penicillins or related drugs (cephalosporins or carbapenems) if adequate alternatives are available. Given the large number of currently available agents with activity against penicillinsusceptible organisms, the need for skin testing and desensitization is now much less common. In the rare cases when it is necessary, however, consultation with an experienced allergist is recommended. Examples of situations where desensitization using progressively larger doses of penicillin, either parenterally or orally, may be necessary include neurosyphilis and syphilis during pregnancy. Patients with a history of an uncomplicated morbilliform or delayed rash after penicillin therapy are not likely to be at risk for immediate hypersensitivity and may be treated with cephalosporins, for which the risk of cross-hypersensitivity to penicillins is likely to be in the range of 5%. Evidence suggests that crosshypersensitivity to aztreonam is less common.

DISTRIBUTION AND EXCRETION Lipid-soluble drugs, such as chloramphenicol and rifampin, penetrate most membranes, including the meninges, more readily than do more ionized compounds, such as the aminoglycosides. Understanding a drug’s distribution, rate and site of metabolism, and route of excretion is essential in selecting the appropriate drug and dose. Drugs excreted unchanged in the urine may be particularly suitable for the treatment of lower urinary tract infection or for the treatment of systemic infection in the presence of renal insufficiency. Some antimicrobials are metabolized in the liver and must be adjusted appropriately in the presence of hepatic dysfunction.

ACTIVITY OF THE DRUG The physician must understand the spectrum of activity of the drug against microbial isolates, the mechanism of activity of the agent, and whether it is bactericidal or bacteriostatic in achievable concentrations. It should be remembered, however, that the actual activity of an agent as bacteriostatic or bactericidal may depend on concentration at the anatomic site, the microorganism involved, or both. As a general rule, cell wall–active drugs are likely to be bactericidal. Bactericidal drugs are necessary for treatment of infections sequestered from effective host inflammatory responses, such as meningitis and endocarditis. With the exception of

Route of Administration Oral administration of antimicrobials can often prevent the morbidity and expense associated with parenteral (intra venous or intramuscular) administration. Although some antimicrobials (e.g., amoxicillin and the fluoroquinolones) are very well absorbed after oral administration, most patients hospitalized with severe infections should be treated, at least initially, with intravenous antibiotics. Gut absorption of antimicrobials can be unpredictable, and the intravenous route often permits administration of greater amounts of drug than can be tolerated orally. Intramuscular administration of some antimicrobials can result in excellent drug absorption but should be avoided in the presence of hypotension (erratic absorption) and coagulation disorders (hematomas). Repeated intramuscular injections are uncomfortable and for some drugs (e.g., pentamidine) can also result in the formation of sterile abscesses.

Duration of Therapy Antimicrobial therapy should be initiated as part of a treatment plan of defined duration. In a few settings, the duration of optimal antimicrobial therapy is established (e.g., 10 days, but not 7 days, of oral penicillin will consistently prevent

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Table 94-1 Characteristics of Commonly Used Antimicrobial Agents Drug Class

Site of Action

Excretion/ Metabolism

Uses and Activity

Cell wall Cell wall

Renal Renal and/or hepatic

Streptococci, Neisseria, oral anaerobes Methicillin-sensitive staphylococci

Cell wall

Renal

Cell wall

Renal

Inactivate β-lactamase

Renal/metabolic

Gram-positive organisms, not staphylococci, some gram-negative organisms Broad-spectrum gram-positive organisms; gramnegative organisms, including Pseudomonas, not Staphylococcus Used with ampicillin, amoxicillin, piperacillin, or ticarcillin; expand activity to include anaerobes, many gram-negative organisms, and methicillinsensitive staphylococci

Cell wall

Renal

Antibacterials β-Lactams Penicillins β-lactamase–resistant penicillins (e.g., nafcillin) Amino penicillins (e.g., ampicillin) Extended-spectrum penicillins (e.g., piperacillin) β-lactamase inhibitors (e.g., clavulanic acid)

Cephalosporinsa First generation (e.g., cefazolin) Second generation (e.g., cefuroxime) Third generation (e.g., ceftriaxone) Fourth generation (e.g., cefepime)

Renal

Renal

Some active against Pseudomonas (e.g., ceftazidime) Broadest spectrum including resistant nosocomial gram-negative organisms, and gram-positive cocci, including methicillin-sensitive staphylococci

Cell wall

Renal

Aerobic gram-negative bacilli

Cell wall

Renal

Very broad-spectrum, many gram-negative, including resistant nosocomial organisms, some enterococci, and methicillin-sensitive staphylococci, anaerobes

Glycopeptides Vancomycin

Cell wall

Renal

Coagulase-positive and coagulase-negative staphylococci, other gram-positive bacteria

Streptogramins Quinupristin-dalfopristin

Ribosome

Hepatic, fecal

Gram-positive organisms, including methicillinresistant staphylococci and non-faecalis vancomycin-resistant enterococci

Lipopeptides Daptomycin

Cell membrane (?)

Renal

Coagulase-positive and coagulase-negative staphylococci, other gram-positive bacteria, including glycopeptide-resistant enterococci

Oxazolidinones Linezolid

Ribosome

Renal

Inhibit nucleic acid synthesis DNA gyrase

Renal

DNA disruption

Hepatic metabolism

Rifampin

Transcription

Aminoglycosides

Ribosome

Hepatic metabolism/ renal Renal

Coagulase-positive and coagulase-negative staphylococci, other gram-positive bacteria, including glycopeptide-resistant enterococci, certain mycobacteria, Nocardia Gram-negative bacilli, Salmonella, Pneumocystis jirovecii, Nocardia Broad spectrum, including Legionella; newer agents also active against streptococci or anaerobes Anaerobes, Clostridium difficile, amebas, Trichomonas Mycobacterium tuberculosis; meningococcal and Haemophilus influenzae prophylaxis Gram-negative bacilli; no activity in anaerobic conditions

Monobactams Aztreonam Carbapenems Imipenem-cilastatin, meropenem, ertapenem, doripenem

Sulfonamides, trimethoprim Fluoroquinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin) Metronidazole

Renal or hepatic

Gram-positive organisms, many common gramnegative bacteria Some with anaerobic activity (e.g., cefoxitin)

Some hepatic metabolism

Chapter 94—Antimicrobial Therapy

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Table 94-1 Characteristics of Commonly Used Antimicrobial Agents—Cont’d Excretion/ Metabolism

Drug Class

Site of Action

Chloramphenicol

Ribosome

Hepatic metabolism/ renal

Clindamycin

Ribosome

Tetracyclines

Ribosome

Hepatic metabolism/ renal Renal/hepatic metabolism

Uses and Activity Broad spectrum; active against Salmonella, anaerobes, Rickettsia, Brucella, Bartonella, but use limited by toxicity Anaerobes; gram-positive cocci Broad spectrum; especially useful for spirochetes, Rickettsia

Glycylcyclines Tigecycline

Ribosome

Renal/hepatic metabolism

Broad spectrum, including methicillin-resistant staphylococci, anaerobes, gram-negative organisms

Macrolides and Azalides Erythromycin Azithromycin, clarithromycin

Ribosome Ribosome

Hepatic Hepatic

Gram-positive cocci, Legionella, Mycoplasma High intracellular levels have enhanced activity against mycobacteria, Toxoplasma

Ribosome

Hepatic metabolism/ renal

Enhanced activity against gram-positive organisms, including methicillin-resistant staphylococci, intracellular respiratory pathogens, macrolideresistant Streptococcus pneumoniae

Ketolides Telithromycin

Antifungals Polyenes Amphotericin B Flucytosine Azoles Ketoconazole

Binds membrane Tissue breakdown ergosterol Blocks DNA synthesis Renal Block ergosterol biosynthesis Hepatic

Itraconazole Fluconazole Voriconazole

Hepatic Renal Hepatic

Posaconazole

Hepatic

Echinocandins Caspofungin

Most fungi; newer lipid formulations may be better tolerated Candidiasis; Cryptococcus with amphotericin B Mucosal candidiasis, pulmonary histoplasmosis (nonmeningeal) Histoplasmosis, blastomycosis Candidiasis, cryptococcosis, coccidioidomycosis Invasive aspergillosis, Fusarium and Scedosporium infections, empiric for febrile neutropenia Prophylaxis of invasive fungal infections in immunosuppressed patients, zygomycosis (not FDA approved), refractory Candida infections

Inhibit glucan synthesis Chemical decay and degradation

Micafungin

Anidulafungin

Chemical decay and degradation

Candida species, invasive aspergillosis Esophageal candidiasis, prophylaxis of invasive Candida infections in bone marrow transplant recipients, empiric treatment in febrile neutropenia Candidemia, other systemic Candida infections, esophageal candidiasis

Antivirals Acyclovir

DNA polymerase

Famciclovir Ganciclovir, valganciclovir Foscarnet Cidofovir Amantadine, rimantadine Zanamavir Oseltamavir Ribavirin Interferon-α Entecavir

DNA polymerase DNA polymerase DNA polymerase DNA polymerase Uncoating(?) Neuraminidase Neuraminidase RNA synthesis(?) Immunomodulator DNA polymerase

Renal

Renal Renal Renal Renal Renal Renal Hepatic/renal Renal

Herpes simplex, including encephalitis; herpes zoster Herpes simplex, zoster Cytomegalovirus, herpesviruses Cytomegalovirus, herpesviruses Cytomegalovirus, herpesviruses Influenza A treatment and prophylaxis Influenza A and B Influenza A and B RSV, hepatitis C (together with interferon-α) Hepatitis B, C Hepatitis B Continued

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Table 94-1 Characteristics of Commonly Used Antimicrobial Agents—Cont’d Drug Class

Excretion/ Metabolism

Uses and Activity

HIV-1 reverse transcriptase

Renal and/or hepatic

HIV-1

HIV-1 reverse transcriptase HIV-1 protease HIV-1 viral entry Cellular CCR5

Hepatic

HIV-1

Hepatic Catabolism Hepatic/renal

HIV-1 HIV-1 HIV-1

HIV-1 integrase

Hepatic

HIV-1

Site of Action

Antiretrovirals Nucleoside or nucleotide reverse transcriptase inhibitorsb Non-nucleoside reverse transcriptase inhibitorsc Protease inhibitorsd Fusion inhibitorse Chemokine receptor inhibitorsf Integrase inhibitorsg a

As a rule. First-generation cephalosporins have better activity against gram-positive cocci and minimal CNS penetration. Second-generation cephalosporins have somewhat better activity against gram-negative bacteria and may penetrate the CNS. Third-generation cephalosporins have broader activity against gram-negative bacteria and generally penetrate the CNS, but they are relatively less active against gram-positive cocci. Fourth-generation cephalosporins have the broadest spectrum of activity, regaining activity against gram-positive organisms. b These include zidovudine, stavudine, didanosine, zalcitabine, lamivudine, emtricitabine, tenofovir, and abacavir. c These include efavirenz, nevirapine, etravirine, and delavirdine. d These include indinavir, nelfinavir, ritonavir, saquinavir, amprenavir, fosamprenavir, tipranavir, atazanavir, darunavir, and lopinavir-ritonavir. e The only currently approved agent is enfuvirtide. f The only currently approved agent is maraviroc. g The only currently approved agent is raltegravir. CNS, central nervous system; FDA, U.S. Food and Drug Administration; HIV, human immunodeficiency virus; RSV, respiratory syncytial virus.

rheumatic fever after streptococcal pharyngitis); in many others the duration of treatment is empirical and sometimes can be based on the clinical and bacteriologic course. Bloodstream infections without endocarditis or other focal infections can generally be treated for 10 to 14 days. Pneumococcal pneumonia can be effectively treated in 7 to 10 days.

Combinations Combinations of antimicrobials are indicated in serious infection when they provide more effective activity against a pathogen than any single agent. In some instances, combinations of drugs are used to prevent the emergence of resistance (e.g., infections caused by Mycobacterium tuberculosis and the human immunodeficiency virus). In others, combinations are used because they provide synergistic action against the pathogen (e.g., penicillin, a cell wall–active antibiotic, facilitates uptake of aminoglycosides by enterococci). In still other instances, drug combinations are used in empirical therapies to cover a wide spectrum of potential pathogens when the causative agent is unidentified or when infection is likely to be from a mixture of organisms (e.g., fecal soilage of the peritoneum). The use of more than one drug increases the likelihood of toxic effects, increases costs, and often increases the risk of superinfection.

Monitoring of Antimicrobial Therapy The physician and patient should be alert to potential toxic effects and should be prepared to halt the drug in the event of serious toxic effects. Similarly, in vitro susceptibility is not necessarily synonymous with clinical effectiveness, and repeated clinical evaluation for resolution of both systemic and local signs of infection is the single most important monitoring tool available to the clinician treating an infectious process. For some antimicrobials, such as aminoglycosides, the ratio of effective to toxic drug levels is low, requiring

monitoring of serum levels of the drug to ensure safe and effective dosing. Vancomycin is another antimicrobial that often requires measurement of serum levels to optimize dosing, particularly with prolonged treatment or in the presence of renal failure.

Antiviral Agents As obligate intracellular pathogens, viruses depend on interactions with host cellular machinery for completion of the life cycle. Thus many potential antiviral treatment strategies are limited by toxic effects on host cells. Specificity for viruses or virus-infected cells can be obtained by interfering with the function of unique viral elements (e.g., the M2 protein of influenza virus that is the target of amantadine and rimantadine) or by developing drugs such as acyclovir that must be processed by viral enzymes (in this instance, phosphorylated by herpesvirus thymidine kinase) before becoming active. In contrast to antibacterial drugs, however, antiviral agents generally have a limited spectrum of activity, each agent being useful against a small number of viruses. In the 1990s there was a dramatic increase in the numbers and types of drugs effective in the treatment of viral infections. This has been particularly striking in the field of antiretroviral therapies (see Chapter 108), and new agents against influenza, hepatitis B, and cytomegalovirus are now part of the therapeutic armamentarium. Additional developments in therapies for other viruses (e.g., hepatitis C) are anticipated.

Antifungal Agents A number of drugs are useful when applied topically or systemically in the treatment of fungal diseases. Most target the ergosterol-containing cell membrane either by inhibiting ergosterol synthesis (azoles) or by aggregating in proximity to ergosterol and increasing membrane permeability (polyenes). Flucytosine inhibits fungal DNA synthesis. Echinocandins inhibit glucan synthesis. Increasing

Chapter 94—Antimicrobial Therapy resistance to certain azoles and flucytosine among clinically relevant fungal isolates limits the utility of these agents in patients requiring chronic therapy.

Antimicrobial Resistance Testing As treatment options expand, the emergence of antimicrobial resistance to therapies is predictable. Thus physicians

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must be prepared to evaluate the resistance patterns of specific microbial isolates. Resistance testing is now routinely provided for bacterial pathogens and in the design of antiretroviral treatment strategies (see Chapter 108). Certain resistance assays are not yet fully standardized, and all require some level of expertise to facilitate their interpretation. Thus interpretation of resistance assay results to guide treatment decisions, whether for serious bacterial, fungal, or viral infections, should generally involve discussion with an expert in infectious diseases.

Prospectus for the Future • Newer classes of antiviral medications targeting hepatitis and other viruses • Newer classes of antiretroviral medications targeting different phases of viral replication • Newer classes of antibacterials targeting antibiotic-resistant organisms

References Craig WA: Antibacterial therapy. In Goldman L, Bennett JC (eds): Cecil Textbook of Medicine, 22nd ed. Philadelphia, Elsevier, 2005, pp 1753-1764. Hayden FG: Antiviral drugs (other than antiretrovirals). In Mandell GL, Bennett JE, Dolin R (eds): Principles and Practice of Infectious Diseases, 6th ed. Philadelphia, Elsevier, 2005, pp 514-551.

• Newer, less toxic antifungal agents • Antimicrobial peptides and other “designer” drugs with innovative mechanisms of action • Improved agents for the treatment of parasitic and other diseases that are uncommon in Western developed countries (e.g., malaria, leishmania)

Moellering RC, Eliopoulos GM: Principles of anti-infective therapy. In Mandell GL, Bennett JE, Dolin R (eds): Principles and Practice of Infectious Diseases, 6th ed. Philadelphia, Elsevier, 2005, pp 242-253.

XVII

Chapter

95

Fever and Febrile Syndromes Tracy L. Lemonovich and Robert A. Salata

Regulation of Body Temperature Although normal body temperature ranges vary considerably, oral temperature readings in excess of 37.8° C (100.2° F) are generally abnormal. In healthy individuals, core body temperature is maintained within a narrow range, so that for each individual, daily temperature variations greater than 1° to 1.5° C are distinctly unusual. The hypothalamic nuclei that establish set points for body temperature control this homeostasis. Homeostasis is affected by a complex balance between heat-generating and heat-conserving mechanisms that raise or lower body temperature, respectively. Heat is regularly generated as a byproduct of obligate energy use (e.g., cellular metabolism, myocardial contractions, breathing). When an increase in body temperature is needed, shivering—nondirected muscular contractions—generates large amounts of heat. Cutaneous blood vessels constrict to diminish heat lost to the environment. At the same time, the person feels cold; this heat preference promotes heatconserving behavior, such as wrapping up in a blanket. Similarly, when a lower body temperature is needed, obligate heat loss to the environment occurs through the skin and by evaporation of water through sweat and respiration. Vasodilation flushes the skin capillaries, temporarily raising skin temperature but ultimately lowering core body temperature by increasing heat loss through the skin to the cooler environment. Sweating promotes rapid heat loss through evaporation, and at the same time the person feels warm and sheds blankets or initiates other activities to promote heat loss.

Fever and Hyperthermia Fever is an elevated body temperature that is mediated by an increase in the hypothalamic heat-regulating set point. Although exogenous substances such as bacterial products may precipitate fever, the increase in body temperature is achieved through physiologic mechanisms. In contrast, 910

hyperthermia is an increase in body temperature that overrides or bypasses the normal homeostatic mechanisms. As a general rule, body temperatures in excess of 41° C (105.8° F) are rarely physiologically mediated and suggest hyperthermia. Hyperthermia may occur after vigorous exercise, in patients with heat stroke, as a heritable reaction to anesthetics (malignant hyperthermia), as a response to phenothiazines (neuroleptic malignant syndrome), and occasionally in patients with central nervous system disorders such as paraplegia (see also Chapter 118). Some patients with severe dermatologic conditions are also unable to dissipate heat and therefore experience hyperthermia. Fever is usually a physiologic response to infection or inflammation. Monocytes or tissue macrophages are activated by various stimuli to liberate various cytokines with pyrogenic activity (Fig. 95-1). Interleukin (IL)-1 is also an essential cofactor in initiating the immune response. Another pyrogenic cytokine, tumor necrosis factor (TNF)–α, activates lipoprotein lipase and may also play a role in immune cytolysis; TNF-β, or lymphotoxin, has similar properties. A fourth cytokine, interferon (IFN)-α, has antiviral activity (see Chapter 92). IL-6, a cytokine that potentiates B-cell immunoglobulin (Ig) synthesis, also has pyrogenic activity. Endogenous pyrogens activate the anterior preoptic nuclei of the hypothalamus to raise the set point for body temperature. Newer data suggest that there is also a more immediate stimulatory effect of exogenous pyrogens (e.g., bacterial lipopolysaccharide) in the production of fever. This occurs when exogenous pyrogens induce the release of prostaglandin E2 (PGE2), which either directly stimulates the anterior preoptic nuclei or causes excitation of vagal afferent nerves that transmit signals to these nuclei. Infection with all types of microorganisms can be associated with fever. Tissue injury with resulting inflammation, as observed in patients with myocardial or pulmonary infarction or after trauma, can produce fever. Certain malignancies such as lymphoma and leukemia, renal cell carcinoma, and hepatic carcinoma are also associated with fever. In some instances, fever is related to the liberation of endogenous pyrogens by monocytes in the inflammatory response surrounding the tumor; in other

Chapter 95—Fever and Febrile Syndromes

Antigen antibody complex

Bacteria and bacterial products

Antigens

T-lymphocyte

Lymphokines

Prostaglandin E2 HYPOTHALAMUS

Endogenous pyrogens (interleukin-1) (Tumor necrosis factor) (Interferon-α)

C5a

911

Increase in body temperature “set point”

Exogenous pyrogens (e.g., bacterial lipopolysaccaride)

Mononuclear phagocyte

Viruses Crystals (e.g., urate)

Fever Figure 95-1 Pathogenesis of fever.

patients, the malignant cell may release an endogenous pyrogen. Many immunologically mediated disorders, such as connective tissue diseases, serum sickness, and some drug reactions, are characterized by fever. In most patients with drug-induced fevers, the mechanisms are unknown. Virtually any disorder associated with an inflammatory response (e.g., gouty arthritis) can be associated with fever. Certain endocrine disorders such as thyrotoxicosis, adrenal insufficiency, and pheochromocytoma can also produce fever. The association of fever with infections or inflammatory disorders raises the question of whether fever is beneficial to the host. For example, IL-1 (an endogenous pyrogen) is critical for initiating the immune response, elevated temperatures marginally enhance certain in vitro immune responses, and some infectious organisms prefer cooler temperatures. It is not certain, however, that fever is helpful to humans in any infectious disease, with the possible exception of neurosyphilis. Fever is deleterious in certain situations. Among individuals with underlying brain disease and even in healthy older persons, fever can produce disorientation and confusion. Fever and the associated tachycardia may compromise patients, especially older individuals with significant cardiopulmonary disease. Fever should be controlled with antipyretics if the patient is particularly uncomfortable or whenever it poses a specific risk to the patient, such as with underlying severe congestive heart failure or myocardial infarction. Heat stroke almost always results from prolonged exposure to high environmental temperatures and humidity, usually occurring in otherwise healthy individuals after strenuous exercise. Heat stroke is characterized by a body temperature greater than 40.6° C (105° F) and is associated with altered sensorium or coma and with cessation of sweating. Rapid cooling is critical to the patient’s survival. Covering the patient with cold (11° C), wet compresses until the core temperature reaches 39° C is the most effective initial therapeutic approach and should be followed by intravenous infusions of fluids appropriate to correct the antecedent fluid and electrolyte losses.

This variation often persists when patients have fever. In certain individuals, fever patterns may be helpful in suggesting the cause of fever. Rigors—true shaking chills—often herald a bacterial process (especially bloodstream infection), although they may occur in patients with viral infections, as well as in those with drug or transfusion reactions. Hectic fevers, which are characterized by wide swings in temperature, may indicate the presence of an abscess, disseminated tuberculosis, or collagen vascular diseases. Patients with non-falciparum malaria may have a relapsing fever with episodes of shaking chills and high fever, which are separated by 1 to 3 days of normal body temperatures and relative well-being. Medications that may have been recently initiated may cause high, constant fevers. Patients with tuberculosis may be relatively comfortable and unaware of a significantly elevated body temperature. Patients with uremia, diabetic ketoacidosis, or hepatic failure generally have a lower body temperature; thus, normal temperature readings in these settings may indicate infection. Similarly, older patients with infection often fail to mount a febrile response and may experience instead a loss of appetite, confusion, or even hypotension without fever. The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen) or corticosteroids also blunts or ablates the febrile response.

FEVER PATTERNS

FEVER ONLY

The normal diurnal variation in body temperatures results in a peak temperature in the late afternoon or early evening.

Most patients with fever as their sole complaint defervesce spontaneously or exhibit localizing clinical or laboratory

Acute Febrile Syndromes Fever is one of the most common complaints that bring patients to a physician. The challenge is in discerning the few individuals who require specific therapy from among the many with self-limited benign illness. The approach is simplified by considering patients in three groups: (1) those with fever without localizing symptoms and signs, (2) those with fever and rash, and (3) those with fever and lymphadenopathy. This chapter deals only with fever caused by microbial agents; however, autoimmune, neoplastic, and other disease processes are important causes of fever as well.

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Table 95-1 Infections Exhibiting Fever as the Sole or Dominant Feature Infectious Agent

Epidemiologic Exposure and History

Distinctive Clinical and Laboratory Findings

Viral Rhinovirus, adenovirus, parainfluenza Enteroviruses

None (adenovirus in epidemics)

Influenza

Winter, epidemic

EBV, CMV Colorado tick fever

See text Southwest and northwest tick exposure

Summer, epidemic

Often URI symptoms; throat and rectal cultures, viral antigen testing Occasionally, aseptic meningitis, rash, pleurodynia, herpangina; serologic or nucleic acid testing Headache, myalgias, arthralgias; nasopharyngeal culture, viral antigen testing See text; monospot test, quantitative nucleic acid testing Biphasic illness, leukopenia; blood, CSF cultures, serologic or nucleic acid testing

Bacterial Staphylococcus aureus Listeria monocytogenes Salmonella Typhi, Salmonella Paratyphi Streptococci

IV drug users, IV catheters, hemodialysis, dermatitis Depressed cell-mediated immunity Food or water contaminated by carrier or patient Valvular heart disease

Must exclude endocarditis; blood cultures

Infected animals

Headache, occasionally pneumonitis, hepatitis, culture-negative endocarditis; serologic testing Headache, myalgias, conjunctival suffusion, biphasic illness, aseptic meningitis; serologic testing

Meningitis may also be present; blood, CSF cultures Headache, myalgias, diarrhea or constipation, transient rose spots; blood, bone marrow, or stool cultures Low-grade fever, fatigue; blood cultures

After Animal Exposure Coxiella burnetii (Q fever) Leptospira interrogans Brucella species Ehrlichia chaffeensis

Water contaminated by urine from dogs, cats, rodents, small mammals Exposure to cattle or contaminated dairy products South and southeast deer or dog tick exposure

Occasionally epididymitis, sacroiliitis, endocarditis; blood cultures, serologic testing Acute onset of headache, fever, myalgias; leukopenia and thrombocytopenia; blood smear, serologic or nucleic acid testing

Granulomatous Infection Mycobacterium tuberculosis Histoplasma capsulatum

Exposure to patient with tuberculosis, known positive tuberculin skin test result Mississippi and Ohio River valleys

Back pain suggests vertebral infection; sterile pyuria or hematuria suggests renal infection; liver or bone marrow cultures, histology Pneumonitis, oropharyngeal lesions; culture and histology of bone marrow and oral lesions, serologic or antigen testing

CMV, cytomegalovirus; CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; IV, intravenous; URI, upper respiratory infection.

findings within 2 to 3 weeks of the onset of illness (Table 95-1). Beyond 3 weeks, the patient can be considered to have a fever of unknown origin (FUO), a designation with its own circumscribed group of management considerations, as discussed later in this chapter.

Viral Infections In young, healthy individuals, acute febrile illnesses generally represent viral infections. The causative agent is rarely established, largely because establishing the precise diagnosis seldom has major therapeutic implications. Rhinovirus, coronavirus, parainfluenza, and adenovirus infections are usually, but not invariably, associated with symptoms of coryza or upper respiratory tract infection (e.g., rhinorrhea, sore throat, cough, hoarseness). Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) infections can range from upper respiratory tract infection to bronchiolitis and severe pneumonia. Human bocavirus is a newly described cause of respiratory tract infections, primarily occurring in children. Enterovirus infections occur predominantly in the summer, usually in an epidemic setting.

Undifferentiated febrile syndromes account for the majority of enteroviral infections, but the etiologic features are more likely to be established definitively when a macular rash, aseptic meningitis, pericarditis, or a characteristic syndrome such as herpangina (vesicular pharyngitis caused by coxsackievirus A) or acute pleurodynia (fever, chest wall pain, and tenderness caused by coxsackievirus B) is present. Serologic surveys also indicate that many arthropod-borne viruses (California encephalitis virus; eastern, western, and Venezuelan equine encephalitis viruses; St Louis encephalitis virus) usually produce mild, self-limited febrile illnesses. West Nile virus, in particular, has recently become a common cause of febrile syndrome (less commonly associated with neurologic manifestations) during the summer months throughout the United States. Influenza causes sore throat, cough, myalgias, arthralgias, and headache in addition to fever; it most often occurs in an epidemic pattern during the winter months. It is unusual, however, for fever to persist beyond 5 days in uncomplicated influenza. The mononucleosis syndromes caused by Epstein-Barr virus (EBV), primary human immunodeficiency virus (HIV)

Chapter 95—Fever and Febrile Syndromes (see Chapter 108), cytomegalovirus (CMV), and (in rare cases) Toxoplasma gondii may sometimes manifest in a typhoidal manner—that is, with high fever but little or no detectable lymph node enlargement. Diagnosis and management are discussed later in the section on generalized lymphadenopathy and mononucleosis syndromes, in keeping with the more typical presentation of these processes. The mononucleosis syndromes are generally self-limited. The need to establish a specific diagnosis therefore is usually not urgent with the exception of acute HIV infection. Viral cultures of the throat and rectum and virus-specific antibodies in acute and convalescent serum samples may allow diagnosis of the specific viral cause. Acute retroviral syndrome (HIV) may require diagnosis through plasma p24 antigen or DNA or RNA polymerase chain reaction (PCR) assays because antibodies are frequently not detectable in the early stages (see Chapter 108). The recognition of other viral syndromes, however, can be critically important. The outbreak of severe acute respiratory syndrome (SARS) in Southeast Asia highlights the importance of early recognition. In the spring of 2003, several people in local hospitals exhibited a variety of complaints that typically included fever and dry cough. Only through the combined efforts of the global medical community was the epidemic contained and the SARS coronavirus identified as the causative agent. Avian influenza is the latest in a series of emerging viruses to pose the threat of widespread infection. Fever is an important element in the early stages of this disease as well.

Bacterial Infections Pathogenic bacteria most commonly cause sepsis or disseminated bloodstream infection (see Chapter 96). Staphylococcus aureus (Web Fig. 95-1) frequently causes sepsis without an obvious primary site of infection. Fever may be the predominant clinical manifestation of the illness. S. aureus sepsis should be considered in patients undergoing intravenous therapy with an indwelling catheter, patients on hemodialysis, intravenous drug users, and patients with severe chronic dermatoses. In the patient with S. aureus bacteremia, the question of whether intravascular infection exists is key in determining the length of therapy. The following risk factors are associated with infective endocarditis (IE): long duration of symptoms, underlying valvular disease, prior endocarditis, absence of removable focus of infection (e.g., intravenous catheter, soft tissue abscess), metastatic sites of infection (e.g., septic pulmonary emboli, arthritis), younger age, history of injection drug use, and new heart murmur. Transesophageal echocardiogram is frequently necessary to evaluate for an endovascular focus in S. aureus bacteremia, especially in patients at high risk for IE (see Chapter 100). Listeria monocytogenes bacteremia is seen predominantly in patients with depressed cell-mediated immunity and is the most common presentation of listeriosis in these hosts. Occasionally a relatively indolent clinical syndrome belies the bacterial cause of S. aureus and L. monocytogenes bacteremia. Enteric fever—typhoid or paratyphoid fever—may also have fever alone as the primary clinical manifestation. The major species producing this syndrome are Salmonella Typhi and Salmonella Paratyphi, both of which have humans as their only reservoir. Salmonella Paratyphi usually produces

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less severe disease than Salmonella Typhi. Disease is acquired by ingesting food or water contaminated with fecal material from a chronic carrier or a patient with typhoid or paratyphoid fever. A large number of bacteria (106 to 108) must be ingested to cause disease in the normal host. Major host risk factors are achlorhydria, malnutrition, malignancy (particularly lymphomas), sickle cell anemia, and other defects in cellular and humoral immunity. Salmonella Typhi penetrates the gut wall and enters the lymphoid follicles (Peyer patches), where it multiplies within mononuclear phagocytes. Primary bacteremia occurs with spread to the reticuloendothelial system (liver, spleen, and bone marrow). After further multiplication at those sites, secondary bacteremia can occur and localize to lesions such as tumors, aneurysms, and bone infarcts. Infection of the gallbladder, particularly in the presence of gallstones, leads to a chronic carrier state. Approximately 2 weeks after exposure, patients develop prolonged fever with chills, headache, and myalgias. Diarrhea or constipation may be present but usually does not dominate the clinical picture. Occasionally, crops of rose spots (2- to 4-mm salmon-colored maculopapular lesions) appear on the upper abdomen but are evanescent. Typhoid fever usually resolves in about 1 month if left untreated. However, complication rates are high because of bowel perforation, metastatic infection, and the general debility of patients, which may last for months. Salmonella Typhi or Paratyphi may be isolated from blood, bone marrow, stool, or rose spots to confirm the diagnosis. Typhoid fever should be treated with third-generation cephalosporins or fluoroquinolones. Localized bacterial infection can be clinically occult and can develop as an undifferentiated febrile syndrome. Intraabdominal abscess, vertebral osteomyelitis, streptococcal pharyngitis, urinary tract infection, IE, and early pneumonia may all cause fever with surprisingly few clinical clues to the location of the infection. Therefore urinalysis, throat and blood cultures, and chest radiography should be performed in the patient who is febrile with features suggestive of a bacterial infection. Eleven cases of inhalational anthrax in the United States in 2001 highlighted this bacterial infection as an important cause of fever without early localizing signs. The illness appeared biphasically with an initial influenza-like illness, followed by sepsis syndrome and severe respiratory distress. All patients had abnormal chest radiographs, with the majority demonstrating pleural effusions, mediastinal widening, and pulmonary infiltrates, with a high rate of positive blood cultures. Early recognition and initiation of appropriate antimicrobial therapy are essential to decreasing mortality. Antimicrobial prophylaxis for individuals with potential exposure is critical, combined with adjunctive postexposure vaccination.

Febrile Syndromes Associated with Animal Exposure Q fever, brucellosis, and leptospirosis are diseases associated with exposure to fluids from infected animals and may have similar clinical presentations. Q Fever Q fever is an under-recognized cause of acute febrile illness. Coxiella burnetii, the causative agent, produces mild

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infection in livestock. Humans are infected by inhalation of aerosolized particles or by contact with hides, placenta, or amniotic fluids from infected animals. The source of animal exposure may go unnoticed. A self-limited febrile illness is the most common presentation of Q fever. Other clinical syndromes include pneumonia, hepatitis, osteomyelitis, and neurologic manifestations. Pneumonia may be found incidentally during the initial febrile illness and is often accompanied by headache. Definitive diagnosis is usually based on a fourfold rise in titer of complement-fixing antibodies between acute and convalescent samples, as C. burnetii is difficult to isolate in culture. The treatment of choice for Q fever is doxycycline. Chronic Q fever may also cause endocarditis, often in the setting of underlying valvular disease or a prosthetic valve. The presence of hepatomegaly, splenomegaly, anemia, and purpuric rash caused by vasculitis in a patient with culture-negative endocarditis may be a clue to this diagnosis. Diagnosis is most often serologic; therapy usually involves prolonged combination antimicrobial therapy including doxycycline. Leptospirosis Humans are infected with Leptospira species, primarily Leptospira interrogans, by exposure to urine from infected animals, usually rodents, small mammals, livestock, dogs, and cats. Indirect exposure is most frequent, occurring by contact with contaminated wet soil or water. Direct contact also occurs in veterinarians, farm workers, hunters, and animal handlers. After an incubation period of approximately 1 week, patients develop chills, high fever, headache, and myalgias. The illness often follows a biphasic course. During the second phase of illness, fever is less prominent, but headache and myalgias are severe; aseptic meningitis is the most important manifestation of the second or immune phase of the illness. Suffusion of the bulbar conjunctivae with visible corkscrew vessels surrounding the limbus is a useful early sign of leptospirosis. Lymphadenopathy, hepatomegaly, and splenomegaly may also occur. Leptospirosis may also pursue a more severe clinical course characterized by renal and hepatic dysfunction and hemorrhagic diathesis (Weil syndrome). Laboratory studies in leptospirosis are often nonspecific but may reveal mild transaminase elevation and increase in serum creatine kinase. Darkfield examination can reveal leptospires in body fluids but has low sensitivity and specificity. Leptospires may also be isolated by culture of blood or cerebrospinal fluid (CSF). The diagnosis is most commonly made serologically by a fourfold rise in the microscopic agglutination test (MAT) antibody titer between acute and convalescent sera. Early antibiotic treatment shortens the duration of fever and may reduce complications. However, to be effective, antibiotics must be initiated presumptively, before serologic confirmation. Intravenous penicillin or ceftriaxone is used for severe disease, and oral doxycycline is effective for mild disease. Brucellosis Brucella species infect cattle (Brucella abortus), pigs (Brucella suis), sheep, and goats (Brucella melitensis). Humans are most commonly exposed occupationally via broken skin, aerosolized particles, or inoculation in the conjunctiva or by ingestion of unpasteurized dairy products. Acute disease is nonspecific and is often characterized by chills, fever, head-

ache, and arthralgias and sometimes by lymphadenopathy, hepatomegaly, and splenomegaly. During the associated bacteremia, any organ may be seeded. Epididymo-orchitis, spondylitis (Web Fig. 95-2) or sacroiliitis, granulomatous hepatitis, and bone marrow involvement are characteristic localized findings. With or without antibiotic treatment of acute infection, brucellosis may relapse or enter a chronic phase, although treatment does reduce the incidence of complications and relapse. Brucella species can be isolated from blood or other normally sterile fluids; however, the diagnosis is often made serologically. Treatment consists of combination therapy with doxycycline plus either rifampin or streptomycin.

Granulomatous Infection Tuberculosis Extrapulmonary and miliary tuberculosis (Web Fig. 95-3) may cause a febrile syndrome. In disseminated tuberculosis, initial chest radiographs may be normal and tuberculin skin tests are often nonreactive. This finding is particularly true in older or immunocompromised patients. Protracted FUO should always suggest this possibility. Liver biopsy and bone marrow biopsy have a high yield in miliary disease. Genitourinary and vertebral tuberculosis may also develop as unexplained fever. However, careful history, urinalysis, intravenous pyelography, and radiographs of the spine should reveal the site of tissue involvement. Extrapulmonary tuberculosis should be treated for the first 2 months with four-drug therapy with isoniazid, rifampin, ethambutol, and pyrazinamide given orally. Thereafter, isoniazid and rifampin are continued for 7 months (longer in patients with skeletal tuberculosis). The ethambutol can be discontinued once the organism is shown to be sensitive to isoniazid. Corticosteroids may be a useful adjunctive measure in the patient with severe systemic toxicity or central nervous system involvement (see Chapter 97). The dose of corticosteroids should be tapered as soon as the patient shows symptomatic improvement. Histoplasmosis Most individuals living in endemic areas in the Mississippi and Ohio River valleys who become infected with Histoplasma capsulatum (Web Fig. 95-4) have a subclinical, selflimited febrile illness as a manifestation of acute pulmonary histoplasmosis (Web Fig. 95-5). Although patients may complain of chest pain or cough, physical examination of the chest is usually unremarkable despite radiographic findings of diffuse infiltrates and mediastinal or hilar adenopathy. Therefore, in the absence of chest radiographs, the lower respiratory tract component of the illness is easily overlooked. Cavitary pulmonary histoplasmosis occurs more insidiously with low-grade fever, productive cough, dyspnea, and weight loss. This syndrome is most likely to occur in older men with underlying chronic lung disease such as emphysema. Isolation of H. capsulatum in culture is variable and depends on specimen source and burden of disease. Serology is often used diagnostically, with a complement fixation (CF) antibody titer of at least 1 : 32 or a fourfold rise in titer being consistent with the diagnosis of acute histoplasmosis. Although spontaneous resolution of symptoms is normal in acute pulmonary histoplasmosis, unusually prolonged illness (more than 4 weeks) may require antifungal

Chapter 95—Fever and Febrile Syndromes treatment with itraconazole or amphotericin B for more severe disease. Progressive disseminated histoplasmosis may occur as a consequence of reactivation of latent infection in immunosuppressed individuals (e.g., those with acquired immunodeficiency syndrome [AIDS]) (see Chapter 108) or may reflect an uncontrolled primary infection. The febrile illness in such patients is protracted. Oropharyngeal nodules and ulcerative lesions are commonly found in disseminated histoplasmosis, biopsy of such lesions permits rapid diagnosis. Serologic studies are less helpful in disseminated histoplasmosis because they are positive in less than one half of patients. Cultures and Gomori-methenamine or Grocott silver stains of bone marrow biopsy specimens can establish the diagnosis. Histoplasma urine antigen detection is a sensitive predictor of disseminated infection. Disseminated histoplasmosis is initially treated with amphotericin B, but patients can often be switched to itraconazole to complete therapy once symptoms resolve. Duration of therapy is often 6 to 12 months, but immunosuppressed patients may require lifelong suppressive therapy. Other Infections Malaria characteristically produces febrile paroxysms that occur every 48 (Plasmodium vivax) to 72 (Plasmodium malariae) hours in some patients. However, during the first few days of illness, the fever may be low grade and sustained or intermittent. The diagnosis should therefore be suggested in all febrile travelers who have returned from endemic areas. Malaria may also occur, albeit rarely, in intravenous drug users and recipients of blood transfusions. Plasmodium falciparum (Web Fig. 95-6) causes a high level of parasitemia and is associated with a high mortality rate unless recognized and treated promptly. Daily fever often occurs in this form of malaria. Although P. vivax and Plasmodium ovale may cause relapsing infection long after primary infection because of latent extra-erythrocytic infection in the liver, the course is milder. Demonstration of parasites in blood smears establishes the diagnosis of malaria. Many, if not most, infectious diseases may exhibit fever as an early finding with subclinical or eventual clinical involvement of specific organ systems. Examples include cryptococcosis, coccidioidomycosis, psittacosis, infection with Legionella species, and Mycoplasma pneumoniae infections. Pulmonary involvement by these infectious agents often produces few signs on physical examination; chest radiographs often reveal more prominent abnormalities than are clinically suggested.

FEVER AND RASH Many of the febrile syndromes already discussed may occasionally be associated with a rash (Table 95-2). This section, however, considers diseases in which rash is a prominent feature of the presentation. The most life-threatening infections associated with fever and rash include meningococcemia, staphylococcal toxic shock syndrome (TSS), and Rocky Mountain spotted fever (RMSF).

Bacterial Diseases Petechial lesions, purpura, and ecthyma gangrenosum are lesions associated with bacteremia (see Chapter 96). Dis-

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Table 95-2 Differential Diagnosis of Infectious Agents Producing Fever and Rash Maculopapular Erythematous Enterovirus EBV, CMV, Toxoplasma gondii Acute HIV infection Colorado tick fever virus Salmonella Typhi Leptospira interrogans Measles virus Rubella virus Hepatitis B virus Treponema pallidum Parvovirus B19 Human herpesvirus 6 Vesicular Varicella-zoster virus Herpes simplex virus Coxsackievirus A Vibrio vulnificus Cutaneous Petechiae Neisseria gonorrhoeae Neisseria meningitidis Rickettsia rickettsii (Rocky Mountain spotted fever) Rickettsia typhi (murine typhus) Ehrlichia chaffeensis Echoviruses Viridans streptococci (endocarditis) Diffuse Erythroderma Group A streptococci (scarlet fever, toxic shock syndrome) Staphylococcus aureus (toxic shock syndrome) Distinctive Rash Ecthyma gangrenosum—Pseudomonas aeruginosa Erythema migrans—Lyme disease Mucous Membrane Lesions Vesicular pharyngitis—coxsackievirus A Palatal petechiae—rubella, EBV, scarlet fever (group A streptococci) Erythema—toxic shock syndrome (Staphylococcus aureus and group A streptococci) Oral ulceronodular lesion—Histoplasma capsulatum Koplik spots—measles virus CMV, cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus.

seminated gonococcemia (Web Fig. 95-7) causes sparse vesiculopustular, hemorrhagic, or necrotic lesions on an erythematous base, typically on the extremities and particularly their dorsal surfaces (see Chapter 107). Meningococcemia is also an important cause of fever and a rash that may range from a few petechiae to, in the most severe cases, purpura fulminans (Web Fig. 95-8). Bacterial toxins produce characteristic clinical syndromes. Pharyngitis or other infections with an erythrogenic toxinproducing Streptococcus (Web Fig. 95-9) may lead to scarlet fever. Diffuse erythema begins on the upper part of the chest and spreads rapidly, although sparing palms and soles. Small red petechial lesions are found on the palate, and the skin has a sandpaper texture caused by occlusion of the sweat glands. The tongue at first shows a yellowish coating and then becomes beefy red. The rash of scarlet fever (Web Fig. 95-10) heals with desquamation. Arcanobacterium haemolyticum can also produce pharyngitis and rash.

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Streptococcal TSS may also occur as a complication of group A streptococcal soft tissue infections. Major manifestations include cellulitis and/or fasciitis with shock, adult respiratory distress syndrome, renal failure, liver abnormalities, coagulopathy, and a generalized erythematous macular rash. Treatment consists of high-dose penicillin and clindamycin, early surgical intervention, supportive measures, and possibly intravenous immunoglobulin (IVIG). The mortality remains high (>30%) even with optimal current therapy. Staphylococcal TSS (Web Figs. 95-11 and 95-12) was first recognized as a distinct clinical entity in 1978, with an increased number of cases seen in the early 1980s associated with the use of hyperabsorbable tampons. S. aureus strains producing TSS toxin (TSST-1) or other closely related exotoxins cause the syndrome. TSST-1 acts as a superantigen by directly binding T lymphocytes to antigen-presenting cells via MHC class II receptors, causing an immense cytokine release and ensuing inflammatory response. Previously, most patients have been 15- to 25-year-old girls and women who use tampons. Emerging settings in which nonmenstrual TSS occurs include use of contraceptive diaphragms, vaginal or cesarean deliveries, nasal surgery, influenza, and recalcitrant desquamative syndrome in patients with AIDS. Superficial staphylococcal infections and abscesses often cause TSS in men. Patients with TSS develop the abrupt onset of high fever (temperature >40° C [104° F]), hypotension, nausea and vomiting, severe watery diarrhea, and myalgias, followed in severe cases by confusion and oliguria. Characteristically, diffuse erythroderma (a sunburn-like rash) with erythematous mucosal surfaces is apparent. Later, intense scaling and desquamation of the skin occur, particularly on the palms and soles. Laboratory abnormalities include elevated levels of liver and muscle enzymes, thrombocytopenia, and hypocalcemia. Diagnosis is based on the clinical findings and requires specific exclusion of RMSF, leptospirosis, measles, and blood or CSF cultures negative for organisms other than S. aureus. Management of the patient consists of restoring an adequate circulatory blood volume by the administration of intravenous fluids, drainage of abscesses or débridement of affected tissues if necessary, and treatment of the staphylococcal infection with vancomycin or nafcillin. Vancomycin is the therapy of choice for known methicillin-resistant S. aureus (MRSA) or until susceptibilities are known. Prevention of recurrence targets avoidance of further tampon use and eliminating staphylococcal colonization of skin and mucosal sites. Decolonization regimens may include intranasal antibiotics such as mupirocin, antiseptic body washes, and systemic antibiotics such as rifampin along with other agents.

Rickettsial Diseases In the United States, several rickettsial diseases are endemic including RMSF (Web Fig. 95-13), rickettsialpox, and murine typhus. Of these, RMSF is the most virulent, with a case-fatality rate of greater than 20% if early appropriate therapy is not given. Although originally described in the western United States, most cases occur in the South Atlantic south-central states. The causative organism, Rickettsia rickettsii, is transmitted from dogs or small wild animals to ticks and then to humans. Infection occurs primarily during warmer months, the periods of greatest tick activity. The tick transmits infection after 6 to 10 hours of feeding and may

be unnoticed. The fulminant onset of severe frontal headache, chills, fever, myalgias, and conjunctivitis occurs after 2 to 14 days; cough and shortness of breath develop in one fourth of patients. The diagnosis may be obscure at the onset. Rash characteristically begins on the third to fifth day of illness as 1- to 4-mm erythematous macules on the hands, wrists, feet, and ankles. Palms and soles may also be involved. The rash may be transient, but it usually spreads to the trunk and may become petechial. Intravascular coagulopathy develops in some patients who are severely ill. Diagnosis and the institution of appropriate therapy must be based on the clinical and epidemiologic findings; delay in treatment may be fatal. Confirmation of the diagnosis is usually retrospective by using an indirect immunofluorescence assay showing detectable serum antibodies during convalescence. Treatment is with doxycycline, given orally or parenterally, or oral tetracycline for 7 days.

Human Ehrlichiosis Human ehrlichiosis is an acute, febrile illness caused most frequently by Ehrlichia chaffeensis (Web Fig. 95-14) (human monocytic ehrlichiosis [HME]) or Anaplasma phagocytophilum (human granulocytic anaplasmosis [HGA]). E. chaffeensis is transmitted by the dog tick Amblyomma americanum (the Lone Star tick) and causes illness with peak incidence in the summer months. Since the disease was first recognized in 1986, cases of HME have been identified most frequently in 21 contiguous southeastern states from Maryland to Texas, but have been documented in 47 states. The illness characteristically begins with fever, chills, headache, and myalgias, with a maculopapular rash occurring in less than one third of cases. Although a wide spectrum of illness exists, roughly one half of clinically recognized cases are associated with pulmonary infiltrates. Laboratory studies often reveal leukopenia, thrombocytopenia, and elevated liver transaminases. Acute respiratory distress syndrome often associated with renal failure may develop, most often occurring in older patients. If the disease is left untreated, the mortality rate may exceed 10% in hospitalized patients. More severe illness is usually associated with older age and immunocompromised status (e.g., from HIV, corticosteroid therapy, organ transplantation). HGA peaks in July and occurs in areas where infected Ixodes ticks are found, including the Northeast, parts of the Midwest, and California. Nine percent of patients have concurrent Lyme disease or babesiosis because the same tick vector transmits these diseases. HGA usually exhibits a nonspecific influenza-like illness with fever, chills, malaise, headache, nausea, and vomiting. As in HME, leukopenia, thrombocytopenia, and elevations in hepatic transaminases are important laboratory features. Older patients tend to have more severe disease. Presumptive diagnosis of HME or HGA is made on clinical grounds in patients with acute febrile illnesses, which are generally associated with decreasing leukocyte and platelet counts after tick exposure. Peripheral blood smears may show intracellular organisms called morulae in infected leukocytes, particularly in HGA. Serodiagnosis is sensitive but helpful only in retrospective confirmation of diagnosis. PCR methods for amplifying nucleic acids of E. chaffeensis and A. phagocytophilum appear to be effective for a timely diagnosis of active infection. Treatment with doxycycline or

Chapter 95—Fever and Febrile Syndromes tetracycline is effective in decreasing both the duration and the severity of illness. Major clinical distinctions between human ehrlichiosis and RMSF include the earlier, more frequent, and more severe cutaneous manifestations of RMSF and the more common pulmonary manifestations and characteristically decreasing leukocyte counts in ehrlichiosis.

Lyme Disease Lyme disease is a common, multisystem spirochetal infection caused by Borrelia burgdorferi (Web Fig. 95-15) and is transmitted by the Ixodes species of ticks, Ixodes scapularis in the East and Midwest US and Ixodes pacificus in California. The largest number of cases are distributed in areas that correspond to distribution of the Ixodes vectors (the Northeast, Wisconsin, Minnesota, California, and Oregon); however, the infection is distributed broadly throughout North America and Western Europe. Between 3 days and 3 weeks after the tick bite, of which most individuals are unaware, patients develop a mild febrile illness, usually associated with headache, stiff neck, myalgias, arthralgias, and erythema migrans (EM) (Web Fig. 95-16). EM begins as a red macule or papule at the site of the tick bite; the surrounding bright red patch expands to a diameter of up to 15 cm. Partial central clearing is often seen. The centers of lesions may become indurated, vesicular, or necrotic, and several red rings may be found within the outer border. Smaller secondary lesions that are caused by disseminated spirochetes may appear within several days. Lesions are warm but nontender. Enlargement of regional lymph nodes is common. The rash usually fades in several weeks without treatment. Several weeks after the onset of symptoms, important neurologic manifestations occur in more than 15% of patients. Most characteristic is meningoencephalitis with cranial nerve involvement and peripheral radiculoneuropathy. Bell palsy may occur as an isolated phenomenon; when associated with fever, this finding is strongly suggestive of Lyme disease. The CSF at this time shows a lymphocytic pleocytosis of approximately 100 cells/mL. Heart involvement may also exhibit as atrioventricular block, myopericarditis, or cardiomegaly. Joint involvement eventually occurs in 60% of untreated patients. Early in the course, arthralgias and myalgias may be quite severe. Months later, arthritis often develops with significant swelling and little pain in one or two large joints, typically the knee. Episodes of arthritis may recur for months or years; in about 10% of patients the arthritis becomes chronic, and erosion of cartilage and bone occurs. Diagnosis is usually based on a compatible clinical syndrome, potential exposure in an endemic area, and positive serologic testing. Serologic testing should not be performed in the setting of EM, as antibodies are likely to be negative in the first 1 to 2 weeks of disease. Serologic testing is performed in a two-step approach with an initial enzyme-linked immunosorbent assay (ELISA), followed by a confirmatory Western blot in those with positive or equivocal ELISA results. By 1 month of disease, essentially all patients with active infection have positive immunoglobulin G (IgG) titers. Antibody responses wane slowly after treatment but may remain present for years after infection. Antibodies to B. burgdorferi may also be detected in CSF in acute neu-

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roborreliosis. In Lyme arthritis, synovial fluid contains an average of 25,000 cells/mL, mostly neutrophils. Synovial fluid PCR for B. burgdorferi DNA provides a moderately sensitive means of diagnosis before antibiotic treatment. Treatment with doxycycline 200 mg orally within 72 hours of a deer tick bite in an endemic area appears to decrease the subsequent development of Lyme disease. Treatment of the early manifestations of Lyme disease with doxycycline or amoxicillin for 14 to 21 days usually prevents late complications. Neurologic and cardiac involvement should be treated with intravenous aqueous penicillin G or ceftriaxone for 14 to 28 days; first-degree atrioventricular block or an isolated facial palsy can usually be treated with an oral regimen. Arthritis can be treated with oral therapy for 30 to 60 days or intravenously for 14 to 28 days.

Viral Infections The rashes associated with viral infections may be so typical as to establish unequivocally the cause of the febrile syndrome (Web Table 95-1). Varicella-zoster requires special consideration because of the availability of effective antiviral drugs. In normal children under the age of 12, antiviral therapy is not required for the treatment of chickenpox. However, for patients over age 12, those with chronic cutaneous or pulmonary disease, those receiving salicylate therapy, and immunocompromised hosts should receive antivirals because these patients are at higher risk for complications. Dermatomal herpes zoster should be treated in those older than age 50 to decrease the incidence, severity, and duration of post-herpetic neuralgia (PHN). Immunocompromised patients with herpes zoster should also be treated to prevent dissemination of infection. In addition, ophthalmic zoster demands antiviral treatment because of its association with vision loss related to the development of keratitis, iridocyclitis, or secondary glaucoma. In general, more severe disease with either chickenpox or herpes zoster requires intravenous acyclovir therapy, whereas milder disease may be treated orally with acyclovir or valacyclovir. Acute onset of high fever characterizes viral hemorrhagic fevers, along with, in some cases, bleeding complications and high mortality rates. Arthropod vectors usually transmit these infections; in some patients, they are acquired by direct contact with the reservoir animal or with infected persons and their body fluids. These illnesses include dengue, Marburg hemorrhagic, Ebola hemorrhagic, and Lassa fevers.

FEVER AND LYMPHADENOPATHY Many infectious diseases are associated with some degree of lymph node enlargement. However, in some diseases, lymphadenopathy is a major manifestation. Lymph node enlargement can be further divided according to whether the enlargement is generalized or regional.

Generalized Lymphadenopathy: Mononucleosis Syndromes The mononucleosis syndromes are important causes of fever and generalized lymph node enlargement. Epstein-Barr Virus Infection Approximately 90% of American adults have serologic evidence of EBV infection; most infections are subclinical and

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Table 95-3 Most Common Infectious Causes of Heterophil-Negative Atypical Lymphocytosis

Table 95-4 Differential Diagnosis of Monospot-Negative Mononucleosis

Babesiosis Chickenpox Cytomegalovirus Epstein-Barr virus (particularly in children) Human herpesvirus 6 Human immunodeficiency virus (especially during acute seroconversion) Infectious mononucleosis Malaria Measles Toxoplasmosis Varicella Infectious hepatitis

Acute HIV infection EBV mononucleosis (particularly in children) Cytomegalovirus Acute toxoplasmosis Streptococcal pharyngitis Acute hepatitis B infection

occur before the age of 5 years or midway through adolescence. EBV causes approximately 80% of clinical cases of infectious mononucleosis. This acute illness usually develops late in adolescence after intimate contact with asymptomatic oropharyngeal shedders of EBV. Patients develop sore throat, fever, and generalized lymphadenopathy and sometimes experience headache and myalgias. From 5% to 10% of patients have a transient rash that may be macular, petechial, or urticarial. Palatal petechiae are often present, as is pharyngitis, which may be exudative. Cervical lymph node enlargement, particularly involving the posterior lymphatic chains, is prominent, although some involvement elsewhere is common. The spleen is palpably enlarged in about 50% of patients. Thrombocytopenia and hepatitis are common laboratory abnormalities. Autoimmune hemolytic anemia, encephalitis or aseptic meningitis, Guillain-Barré syndrome, and splenic rupture are rare but severe complications of EBV infection. The enlarged spleen may be very fragile, necessitating avoidance of contact sports and caution in splenic palpation. Three fourths of patients exhibit an absolute lymphocytosis. At least one third of their lymphocytes are atypical in appearance: large, with vacuolated basophilic cytoplasm, rolled edges often deformed by contact with other cells, and lobulated, eccentric nuclei. Immunologic studies indicate that some circulating B cells are infected with EBV and that the cells involved in the lymphocytosis are mainly reactive cytotoxic T cells. Atypical lymphocytes may also be seen in other viral illnesses (Table 95-3). B-cell infection with EBV is a stimulus to the production of polyclonal antibodies. Heterophile antibody tests such as the Monospot rapid diagnostic test are sensitive and specific; false-positive results occur in rare cases in patients with lymphoma or hepatitis. Virus-specific antibodies also are produced in response to infection. The presence of IgM antibody to viral capsid antigen (VCA) is virtually diagnostic of acute infectious mononucleosis. The appearance of antibody to EBV nuclear antigen occurs late in the course of infection and is also indicative of recent EBV infection. These antibodies persist lifelong. Infectious mononucleosis usually has a benign course with complete recovery even in patients with neurologic involvement, and fatalities are rare. The fever resolves after

EBV, Epstein-Barr virus; HIV, human immunodeficiency virus.

1 to 2 weeks, although residual fatigue may be protracted. In general, patients should be managed symptomatically. Antibiotics, particularly ampicillin, should be avoided as the use of ampicillin causes a classic rash in almost all patients with EBV infection. This phenomenon can also be a diagnostic clue to the occurrence of EBV infection. Because EBV infection is predominantly latent, there is no role or available antiviral therapy directed against EBV. Corticosteroids are indicated in the rare individual with serious hematologic involvement (e.g., thrombocytopenia, hemolytic anemia) or impending airway obstruction as a result of massive tonsillar swelling. Acute bacterial superinfections of the pharynx and peritonsillar tissues should be considered when the course is unusually septic. Rarely, patients can have a persistent or recurrent syndrome with evidence of ongoing organ dysfunction including hemophagocytosis, lymphadenitis, hepatitis, and interstitial pneumonia with serologic evidence of chronic active EBV infection. In contrast to the majority of patients with acute infectious mononucleosis, these patients have a poor prognosis. The differential diagnosis of Monospot-negative mononucleosis is shown in Table 95-4. Cytomegalovirus Serologic surveys indicate that by adulthood most people have been infected with CMV, but seroprevalence varies by country. In the United States, 60% to 70% of the population has been infected, and this approaches 100% in some parts of Africa. The ages of peak incidence of CMV infection are in the perinatal period (transmission via the birth canal or by breast milk) and during the second to fourth decades of life. Congenital CMV acquired in utero is usually a result of primary infection in the mother and can be fatal. Like other herpesviruses, CMV can establish latency after primary infection, leading to a potential for reactivation. This is often related to immune suppression. There are several important modes of transmission in adults. CMV can be transmitted sexually, and virus can be isolated from both semen and the uterine cervix. The frequency of antibody to CMV and active viral excretion has been shown to correlate with number of sexual partners. Contact with oral secretions and fecal-oral transmission are the main sources of CMV infection within households and in child day-care workers. In addition, blood transfusions carry a risk of approximately 3% per unit of blood for transmitting CMV infection. This risk becomes substantial in the setting of open-heart surgery or multiple transfusions for other indications. The use of seronegative or

Chapter 95—Fever and Febrile Syndromes leukocyte-depleted blood products can minimize the risk of CMV transmission, particularly in high-risk CMV seronegative hematopoietic stem cell transplant recipients. Primary infection with CMV causes a major proportion of cases of Monospot-negative mononucleosis (see Table 95-4). The distinction between CMV and EBV may be impossible on clinical grounds alone. However, CMV tends to involve older patients (mean age 29) and often produces milder disease, is less likely to cause pharyngitis, and often causes high fever with little or no peripheral lymph node enlargement. The infrequent but serious forms of neurologic and hematologic involvement that develop in EBV infection occur less commonly with CMV. As with EBV infection, hepatitis (which is usually mild and may be granulomatous) is common. Diagnosis of primary infection is usually made serologically by indirect fluorescent or CF antibody testing. The IgM antibody in particular is specific for primary infection. Isolation of CMV from body fluids or tissues can also be diagnostic in primary or reactivation of latent infection. CMV hybrid capture and PCR techniques have been developed to provide rapid laboratory diagnosis of CMV viremia and can be useful in certain patient groups such as solid organ or hematopoietic stem cell transplant recipients. CMV mononucleosis is usually a self-limited disease that does not require specific therapy. CMV infection in the immunocompromised host may be life threatening; in this setting it usually responds to therapy with ganciclovir, valganciclovir, or foscarnet. Primary HIV Infection (Acute Retroviral Syndrome) Typical presenting features of primary HIV infection overlap those of the mononucleosis syndrome (see Chapter 108). Although most patients with the acute retroviral syndrome seek medical attention, the correct diagnosis is missed in a large number of cases because of physician failure to consider HIV infection. Because it is of critical importance to both the patient and his or her sexual partners to establish this diagnosis (see Chapter 108), primary HIV infection must be considered in all patients with mononucleosis syndromes. Toxoplasmosis T. gondii is a parasite of cats and other felids. T. gondii is acquired in humans by ingestion of tissue cysts in undercooked meat, by ingestion of food or water contaminated by oocysts, or congenitally. Seroprevalence of T. gondii infection varies geographically, with rates in Western Europe and Africa being much higher than in the United States. Overall age-adjusted seroprevalence in the United States has been reported to be 22.5%. Seropositivity in HIV-infected patients in the United States is similar to that in the non–HIVinfected population. Only between 10% and 20% of infections in normal adults are symptomatic. Presentation may take the form of a mononucleosis-like syndrome, although maculopapular rash, abdominal pain caused by mesenteric and retroperitoneal lymphadenopathy, and chorioretinitis may also occur. Striking lymph node enlargement and involvement of unusual chains (occipital or lumbar) may necessitate lymph node biopsy to exclude lymphoma. More commonly, cervical adenopathy is observed in symptomatic patients. Overall, however, toxoplasmosis accounts for less than 1% of mononucleosis-like illnesses. Histologically,

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focal distention of sinuses with mononuclear phagocytes, histiocytes blurring the margins of germinal centers, and reactive follicular hyperplasia indicate Toxoplasma infection. Acute acquired toxoplasmosis is suggested by the conversion of T. gondii–specific IgG and IgM antibodies from negative to positive; several different serologic tests are available including the Sabin-Feldman dye test, indirect fluorescent antibody test, and ELISA. Acute acquired toxoplasmosis is generally self-limited in the immunologically intact host and does not require specific therapy. Significant involvement of the eye or viscera is an indication for treatment with pyrimethamine plus sulfadiazine. Infection in immunocompromised hosts usually reflects reactivation of latent infection rather than acute acquired infection. Clinical manifestations are protean and often severe, the most common being encephalitis, pneumonitis, and myocarditis. Treatment with combination antimicrobial therapy is necessary. Granulomatous Disease Disseminated tuberculosis, histoplasmosis, and sarcoidosis may be associated with generalized lymphadenopathy, although involvement of certain lymph node chains can predominate. Lymph node biopsy shows granulomas or nonspecific hyperplasia.

Regional Lymphadenopathy Pyogenic Infection S. aureus and group A streptococcal infections produce acute suppurative lymphadenitis. The most frequently affected lymph nodes are submandibular, cervical, inguinal, and axillary, in that order. Involved nodes are large (>3 cm), tender, and firm or fluctuant. Pyoderma, pharyngitis, or periodontal infection may be present at the presumed primary site of infection. Patients are febrile and have leukocytosis. Fluctuant nodes should be aspirated. Otherwise, antibiotic therapy should be directed toward the most common pathogens. Penicillin G therapy is appropriate if pharyngeal or periodontal origin implicates a streptococcal or mixed anaerobic infection. Skin involvement suggests possible staphylococcal infection and is an indication for vancomycin or an oral antimicrobial with activity against MRSA (e.g., clindamycin, doxycycline, or trimethoprim-sulfamethoxazole) until susceptibilities are known. The dose and route of administration of the drug should be determined by the severity of the infection. Tuberculosis Scrofula, or tuberculous cervical adenitis, develops in a subacute to chronic fashion. Fever, if present, is low grade. A large mass of matted lymph nodes is palpable in the neck. In children, if Mycobacterium tuberculosis is the causative organism, then other sites of active infection are usually present from ongoing primary infection. In adults, extranodal disease is rare. The most common causative agent of lymphadenitis in children in the United States is Mycobacterium avium complex, followed by Mycobacterium scrofulaceum. Surgical excision is the treatment of choice and usually does not require chemotherapy. Cat-Scratch Disease Chronic regional lymphadenopathy after exposure to a cat scratch, lick, or bite should suggest the diagnosis. About 1

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week after contact with the cat, a local papule or pustule may develop. One week later, regional adenopathy appears, usually of the head, neck, or upper extremity. Lymph nodes may be tender (sometimes exquisitely so) or just enlarged (1 to 7 cm). Fever is low grade if present at all. Lymph node enlargement usually persists for several months. The diagnosis can usually be established on clinical grounds. Lymph node biopsy shows necrotic granulomas with giant cells and stellate abscesses surrounded by epithelial cells. Pleomorphic gram-negative bacilli of Bartonella henselae can be identified in the lymph node biopsy specimens by a Warthin-Starry stain during the first 4 weeks of illness. Serologic testing can confirm the diagnosis. The course is usually self-limited and benign in immunocompetent individuals even without antimicrobial therapy but may be life threatening in persons with severe immunodeficiency. The best approach to the treatment of cat-scratch disease in the immunocompromised patient is not known, but erythromycin, azithromycin, or doxycycline may be helpful. Ulceroglandular Fever Tularemia is the classic cause of ulceroglandular fever. The syndrome is acquired by contact with tissues or fluids from an infected animal (including rabbits, beavers, squirrels, or birds) or the bite of an infected tick. Patients have chills, fever, an ulcerated skin lesion at the site of inoculation, and painful regional adenopathy. When infection is acquired by contact with animals, the skin lesion is usually on the fingers or hand, and lymph node involvement is epitrochlear or axillary. In tick-borne transmission, the ulcer is on the lower extremities, perianal region, trunk, head, or neck and the adenopathy is inguinal, femoral, occipital, or cervical. Most cases are diagnosed serologically, because Gram-stained preparations are usually negative; however, the causative organism, Francisella tularensis, may be isolated from blood, lymph nodes, and other body fluids if supportive media are used. F. tularensis is hazardous to laboratory personnel, who should be notified if this organism is suspected. A fourfold rise in agglutination titer between acute and convalescent serum confirms the diagnosis. PCR techniques for rapid diagnosis have also been developed and may be more sensitive than culture. Patients should be treated with streptomycin as the drug of choice for 7 to 14 days. Quinolones, doxycycline, and chloramphenicol are alternative agents with activity against F. tularensis. Oculoglandular Fever Conjunctivitis with preauricular lymphadenopathy can occur in tularemia, cat-scratch disease, sporotrichosis, lymphogranuloma venereum infection, listeriosis, and epidemic keratoconjunctivitis caused by adenovirus. Inguinal Lymphadenopathy Inguinal lymphadenopathy associated with sexually transmitted diseases (see Chapter 107) may be bilateral or unilateral. In primary syphilis, enlarged nodes are discrete, firm, and nontender. Early lymphogranuloma venereum causes tender lymphadenopathy with later matting of involved nodes and sometimes fixation to overlying skin, which assumes a purplish hue. The lymphadenopathy of chancroid is most often unilateral, is very painful, and is composed of fused lymph nodes. Tender inguinal lymphadenopathy

also occurs in primary genital herpes simplex virus infection. Plague Bubonic plague usually causes fever, headache, and a large mat of inguinal, axillary, or cervical regional lymph nodes near the site of the infected flea bite, which go on to suppurate and drain spontaneously. Plague, caused by Yersinia pestis, is an important consideration in the acutely ill patient in the southwestern United States with possible exposure to fleas and rodents. If plague is suggested, then blood cultures and aspirates of the buboes should be obtained, and streptomycin therapy should be instituted. Gram-stained preparations of the aspirate reveal gram-negative coccobacilli in two thirds of patients. A Wayson stain will reveal the characteristic safety-pin appearance of Y. pestis with dark blue staining polar bodies. Various serologic tests also allow for a rapid specific diagnosis as soon as 5 days after the onset of illness. Both plague and tularemia are potential bioterrorism agents.

Fever of Unknown Origin Fever of unknown origin is the term applied to febrile illnesses with temperatures exceeding 38.3° C (101° F) that are of at least 3 weeks’ duration and remain undiagnosed after 3 days in the hospital or after three outpatient visits. Improvements in noninvasive diagnostic testing have resulted in newly proposed categories of FUO (Table 95-5). They include (1) classic FUO, for which the common causes are infections, malignancy, rheumatologic or connective tissue diseases, and drug fever; (2) nosocomial FUO; (3) neutropenic (38° C or ≤36° C; tachycardia >90 beats/minute; respiratory rate >20 breaths/minute; Paco2 ≤ 32; white blood cell (WBC) count >12,000 cells/mm3 or 10% bands

Refractory septic shock Systemic inflammatory response syndrome (SIRS)

Pathophysiology

Renal failure Hepatic failure

Cardiovascular insufficiency

Pathogenic microorganism

Local Systemic inflammatory inflammatory response response

Systemic inflammatory response plus evidence of inadequate organ perfusion

Metabolic failure Gastrointestinal failure

Death

Immune system failure Respiratory insufficiency

Central nervous system failure Hematologic failure

Clinical entity

Local infection

Sepsis

Sepsis syndrome

Adult respiratory distress syndrome Figure 96-1 Natural history of the sepsis process.

influenced survival in the setting of BSI have included severity of underlying disease, delayed initiation of appropriate antimicrobial therapy, virulence of the pathogen (e.g., P. aeruginosa), extremes of age, site of infection (respiratory being more common than abdominal, which is more common than urinary), health care–associated infection, polymicrobial infection, and development of end-organ complications (acute respiratory distress syndrome, acute renal failure, disseminated intravascular coagulation [DIC], bowel ischemia or infarction, and coma). When evidence of dysfunction of two or more systems exists, the diagnosis of multi-organ system failure can be made. Mortality rises in proportion to the number of organ systems involved and is near 100% when four or more systems are dysfunctional.

Septic shock

Multi-organ failure

Pathogenesis The pathogenesis of sepsis is shaped largely by the infected host’s complex response to the invading pathogen (Fig. 96-2). Sepsis with organ dysfunction occurs primarily when the host’s responses to infection are inadequate. Gramnegative bacterial lipopolysaccharide (LPS), or endotoxin, is representative of a larger class of microbial products causally linked to septic shock syndrome. Cell wall products of gram-positive bacteria, such as teichoic acid and peptidoglycan, induce inflammatory responses similar to those produced by LPS. Sepsis syndrome may complicate infections with bacteria, viruses, fungi, rickettsiae, mycobacteria, and parasites. The pathogenesis of shock involves a series of

Chapter 96—Bacteremia and Sepsis Syndrome

(macrophages, mast cells, dendritic cells) detect molecules on the invader’s cell wall by means of pattern-recognition receptors such as CD14 and toll-like receptors (TLRs). For example, TLR-2 recognizes the peptidoglycan of grampositive bacteria, TLR-4 recognizes an LPS of gram-negative bacteria, and both TLR-2 and TLR-4 recognize the cell wall of Aspergillus. Binding of TLRs to epitopes on the microorganisms stimulates intracellular signaling and leads to the production of cytokines and inflammatory molecules such as tumor necrosis factor (TNF)–α and interleukin (IL)-1β. These molecules in turn activate neutrophils and endothelial cells, which results not only in killing of microorganisms but also damaging of endothelium by release of mediators that increase vascular permeability. Edema fluid then flows into the lungs and other organs, causing acute organ injury. Activated endothelial cells also release nitric oxide, a potent vasodilator. Microorganisms stimulate adaptive immune responses in the course of sepsis. B cells release immunoglobulins that bind the microorganisms and promote their delivery by antigen-presenting cells to natural killer cells and neutrophils. Type 1 helper T cells (Th1 cells) secrete proinflammatory cytokines, whereas type 2 helper T cells (Th2 cells) release anti-inflammatory cytokines such as IL-4 and IL-10, depending on the infecting organism and other complex cell-cell interactions (Table 96-3). Systemic inflammation influences activity of the coagulation system by directly and indirectly modulating production of procoagulant and anticoagulant molecules. In response to proinflammatory cytokines, tissue factor released by endothelium and associated thrombin formation, respectively, activate the extrinsic and intrinsic pathways of coagulation. Simultaneous depletion of endogenous anticoagulant molecules occurs, including proteins C and S, tissue factor pathway inhibitor, and antithrombin III, as well as

events initiated by the invading pathogen or its products, and shock is produced through a causally related sequence of host responses. The sepsis cascade begins when a pathogenic microor ganism penetrates a host barrier. Local host defense cells Table 96-2 Microorganisms Involved in Sepsis Syndrome in Relation to Host Factors Organisms of Particular Importance

Host Factors Asplenia

Encapsulated organisms: Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Capnocytophaga canimorsus Vibrio, Yersinia, and Salmonella species, other gram-negative rods, encapsulated organisms Klebsiella species, Streptococcus pneumoniae Mucormycosis, Pseudomonas species, Escherichia coli Tuberculosis, fungi, herpesviruses Enteric gram-negative rods, Pseudomonas, Aspergillus, Candida, Mucor species, Staphylococcus aureus, Streptococcal species Listeria, Salmonella, and Mycobacterium species, herpesvirus group (herpes simplex virus, cytomegalovirus, varicella-zoster virus) Salmonella, Staphylococcus aureus (including MRSA), Mycobacterium avium complex

Cirrhosis Alcoholism Diabetes Steroids Neutropenia

T-cell dysfunction

AIDS

MRSA, methicillin-resistant Staphylococcus aureus.

Binding of lipopolysaccharide of gram-negative bacilli CDI4 TLR-2

Endothelium Binding of pepitidoglycan of gram-positive bacilli Transcription of immunomodulatory cytokines (TNF-α, interleukin-1β, interleukin-10)

TLR-4

NFKB

Release of NF-KB and transfer to nucleus

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Sepsis Activation and binding of macrophage

Increased activity of INOS

Increased NO NO

Vasodilation Figure 96-2 Inflammatory response to sepsis.

Prostaglandins Leukotrienes Proteases Oxidants

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Table 96-3 Cytokines with a Potential Role in Systemic Inflammatory Response Syndrome Cytokine

Source

Target Cell

Function

Granulocytemacrophage colony-stimulating factor (GM-CSF) Granulocyte colonystimulating factor (G-CSF) IL-1 (α and β)

T cells, macrophages, endothelial cells, fibroblasts

Myeloid precursor cells, neutrophils, eosinophils, macrophages Neutrophils, promyelocytes

Proliferation of progenitor cells Differentiation and maturation of neutrophils and macrophages

Fibroblasts, T cells, monocytes, neutrophils

IL-2

Activated T cells

Activated lymphoid cells

IL-4

Th2 T cells

B and T cells, macrophages, mast cells

Induces cytokines (IL-2, IL-3, IL-6, TNF); induces B- and T-cell activation, growth, and differentiation Synthesis of acute phase reaction; induces fever, catabolism Enhances T- and B-cell immune responses Promotes cytotoxic T cells Induces IFN-γ and TNF Induces B-cell activation, proliferation, and differentiation and IgG1 and IgE production

IL-6

Macrophages, fibroblasts, Th2 T cells

Lymphocytes, monocytes

IL-8

Neutrophils, monocytes

IL-12

Monocytes, fibroblasts, endothelial cells Macrophages, B cells

IFN-γ

T cells

Macrophages, monocytes, T and B cells

TNF-α (cachectin), TNF-β (lymphotoxin)

Monocytes, macrophages, lymphocytes, mast cells

Monocytes, macrophages, lymphocytes, neutrophils, fibroblasts

Monocytes, endothelial cells, fibroblasts, neutrophils Macrophages, fibroblasts, T cells, endothelial cells, hepatocytes

T cells

Proliferation of myeloid progenitor cells Enhanced neutrophil survival and function

Enhances MHC class I and II receptors Stimulates B-cell growth, differentiation, and activation Induces synthesis of acute phase reactants Enhanced neutrophil activity and histamine release Induces differentiation of Th1 cells Initiates production of IFN-α Pronounced monocyte and macrophage activation Increased MHC class II expression Induces cascade of inflammatory reactions (fever, catabolism, acute phase reactants)

Induces multiple cytokines (IL-1, GM-CSF) Increases MHC class I expression Enhances B-cell proliferation and immunoglobulin production

IFN, interferon; IgE, immunoglobulin E; IgG1, immunoglobulin G1; IL, interleukin; MHC, major histocompatibility complex; TNF, tumor necrosis factor.

inhibition of fibrinolysis via increases in plasminogen activator inhibitor and thrombin-activatable fibrinolysis inhibitor. Endotoxin stimulates membrane phospholipid metabolism, leading to the generation of platelet-activating factor and other bioactive metabolites of arachidonic acid, including prostaglandins and leukotrienes. These compounds, in turn, exert a variety of synergistic and antagonistic effects on vascular endothelium, smooth muscle, platelets, and leukocytes. The resultant exaggerated procoagulant state leads to microvascular thrombosis (often in association with DIC) and tissue ischemia and may ultimately cause multiple organ failure. These proinflammatory and procoagulant responses are amplified by secondary ischemia and hypoxia through the release of plasminogen-activator inhibitor 1. Proinflammatory cytokines can also lead to host immunosuppression by causing apoptosis of circulating and tissue lymphocytes. The altered signaling pathways in sepsis eventually lead to tissue injury and multiple organ failure. It is therefore critical to interrupt the sepsis cascade early by containing and eliminating the source (e.g., through antibiotics, removal of

infected devices, and drainage of infected fluid or pus). Multiple studies have shown an association between high circulating levels of proinflammatory markers and survival.

Clinical Manifestations The clinical manifestations of sepsis syndrome are protean and often nonspecific (Table 96-4). The clinician is faced with the challenge of early recognition and sorting through the various possible causes of SIRS so that appropriate therapy can be initiated. Patients with the clinical picture of sepsis of uncertain origin should be presumed to have BSI and treated accordingly. Prompt, thorough cultures of blood and suspicious local sites should be followed immediately by initiation of antibiotics appropriate for the most likely pathogens as well as control of the source of infection (removal of infected devices and drainage of infected collections) if at all possible. Fever and chills are usually present, but older or debilitated patients (especially those with renal or liver failure or

Chapter 96—Bacteremia and Sepsis Syndrome Table 96-4 Signs and Symptoms Indicative of Sepsis Syndrome Fever (core temperature >38° C) Hypothermia (core temperature ≤36° C) Chills Hyperventilation (mixed venous oxygen saturation >70%) Mental status changes Hypotension (systolic blood pressure ≤90 mm Hg or mean arterial pressure ≤70 mm Hg) Leukopenia (white blood cell count 12,000 cells/mm3 or >10% bands) Thrombocytopenia (platelet count ≤100,000/mm3) End-organ failure: lung, kidney, liver, heart, disseminated intravascular coagulation, bowel Hypoglycemia or hyperglycemia Hyperlactatemia (>3 mmol/L)

those receiving systemic corticosteroids) may not develop fever. Hypothermia may occur and is associated with a poorer prognosis. One of the early clues to a systemic infectious process is the presence of hyperventilation and respiratory alkalosis. Skin manifestations in sepsis can occur with any infectious agent and at times may represent the earliest signs of sepsis syndrome. Staphylococci and streptococci can be associated with cellulitis or diffuse erythroderma in association with toxin-producing strains. BSI with gram-negative bacteria can be associated with a skin lesion called ecthyma gangrenosum (round or oval 1- to 15-cm lesions with a halo of erythema and usually a vesicular or necrotic central area). Although ecthyma gangrenosum is most commonly associated with P. aeruginosa, other invaders such as Aeromonas organisms, Klebsiella organisms, E. coli, Serratia species, and fungal organisms may also cause ecthyma gangrenosum (see also Chapter 101). Neisseria meningitidis bacteremia is often heralded by petechial and hemorrhagic skin lesions and followed by rapidly progressive shock. The sepsis syndrome is characteristically associated with hypotension and oliguria. In many patients, hypotension may initially respond to intravenous fluids. Other patients progress from an initial stage of hypotension, tachycardia, and vasodilation (warm shock) to deep pallor, vasoconstriction, and anuria (cold shock). Of all infectious causes of sepsis syndrome, gram-negative bacilli most often cause shock; up to 35% of patients with gram-negative sepsis develop shock, often with mortality rates between 40% and 70%. As sepsis syndrome progresses, myocardial function can become profoundly depressed. This situation greatly complicates fluid management and necessitates continuous cardiopulmonary monitoring in an intensive care setting. Pulmonary complications of sepsis syndrome are frequent. Acute respiratory distress syndrome, characterized by arterial oxygen tension less than 50 mm Hg despite fractional inspired oxygen greater than 50%, diffuse alveolar infiltrates, and pulmonary capillary wedge pressure less than 18 mm Hg, occurs in 10% to 40% of patients with sepsis syndrome and is most frequently seen in conjunction with gram-negative

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organisms. Increased pulmonary capillary permeability, resulting from inflammatory cytokines released during sepsis, is a major causative factor in acute respiratory distress syndrome and makes administration of intravenous fluids, often given in an attempt to improve cardiac output, extremely hazardous. Failure of respiratory muscles can also complicate sepsis and contribute significantly to morbidity and mortality. Most patients with sepsis have a neutrophilic leukocytosis. Leukopenia may occur, most often with overwhelming bacteremias but also with severe systemic viral infections. Alcoholics and older adults are at increased risk for sepsis-associated neutropenia. A low platelet count and evidence of coagulopathy occur in up to 75% of patients with gram-negative bacillary bacteremia. DIC occurs in roughly 10% of patients with sepsis. Renal insufficiency in sepsis syndrome is multifactorial and depends to varying degrees on the host, the microbe, and the therapy administered. Most often in sepsis, acute tubular necrosis is the basis for renal dysfunction and may be secondary to hypotension, volume depletion, or cytokines elaborated in sepsis syndrome. Acute renal failure associated with sepsis syndrome may be seen without overt hypotension. Tubulointerstitial disease caused by specific pathogens and/or antimicrobial therapy may also occur. Endocarditis may also be associated with immune complex–mediated glomerulonephritis. Upper gastrointestinal tract bleeding may be a lifethreatening complication in patients with sepsis who also have coagulopathy and thrombocytopenia. Liver dysfunction may occur with evidence of cholestatic jaundice or of hepatocellular injury. With bacteremia related to gramnegative bacilli, hyperbilirubinemia of sepsis often occurs, with little change in the other liver enzymes. Large increases in transaminase values usually indicate ischemia of the liver; these abnormalities usually resolve rapidly with restoration of blood pressure. Increased serum lactate concentrations are seen in patients with severe sepsis and septic shock. Such increases occur as a consequence of increased glycolysis and pyruvate production. Impaired hepatic clearance of lactate and mitochondrial dysfunction also contribute to hyperlactatemia. Hypoglycemia may complicate sepsis syndrome and can be a correctable cause of mental status change or seizures. Hypoglycemia occurs more frequently in individuals with underlying liver disease. Hyperglycemia may result during the body’s acute metabolic response to infection, especially in diabetics or when glucose-containing intravenous fluids are given.

Diagnosis The initial evaluation of the patient with possible sepsis syndrome ideally begins with a thorough history. However, in patients with fully developed sepsis syndrome, the working diagnosis is made on the basis of physical findings, and the detailed history must necessarily follow correction of hemodynamic problems, obtaining appropriate microbial culture samples, and empiric initiation of antimicrobial therapy. Attention should be focused on underlying diseases or predispositions to sepsis, previous infections and

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antimicrobial therapy, available microbiologic information, and symptoms suggesting localization of infection. A history of travel, environmental exposure, and any contact with infectious agents should be thoroughly explored. Information on the complications of previous treatment (e.g., toxic effects of drugs or drug allergies) can be critical in the selection of therapy. Physical examination should focus on discovering clues to infection and localizing sites thereof. Appropriate specimens for microbiologic evaluation must be obtained. Two or three sets of blood cultures from patients with bacteremia yield the organism in 89% and 99% of patients, respectively. The selection of additional laboratory studies should be based on the clinical manifestations. Patients with diarrhea should have a stool sample sent for a cytotoxic assay against Clostridium difficile toxins A and B. Obtaining appropriate diagnostic studies expeditiously is critical. These studies are usually aimed at delineating the focus of infection (e.g., cerebrospinal fluid examination, computed tomography scans) and determining whether adjunctive surgical therapy (e.g., abscess drainage, foreign body removal) is indicated. Patients whose condition is too unstable for transport to the radiology department may benefit from ultrasonography at the bedside.

Therapy The key to managing sepsis is the early recognition of the systemic response and initiation of therapy before hypotension and complications ensue (Table 96-5). Patients with sepsis syndrome, especially if hypotensive, are best managed in the intensive care unit. The essential therapies of sepsis syndrome and septic shock include judicious fluid administration, oxygen, vasopressors, and antibiotics. Early goal-directed therapy focused on optimal oxygen delivery to tissues is associated with improved survival. This therapy includes crystalloid fluid resuscitation, red blood cell transfusion to maintain a hematocrit of at least 30%, careful hemodynamic monitoring, and the use of inotropes in select persons. Antibiotic choices should reflect epidemiologic concerns (see Table 96-2), antibiotic resistance patterns, and potential sites of infection. Time does not allow withholding antimicrobial therapy until bacteremia or an infectious source is proved in patients with sepsis syndrome. Until culture results and other diagnostic studies are completed, empiric broad-spectrum antimicrobial therapy (covering both gram-positive and gram-negative pathogens, as well as antifungal therapy in select patients) is necessary in patients with sepsis (Table 96-6). Initiation of appropriate empiric antimicrobial therapy has a major impact on survival of these patients. As soon as a specific microbial cause has been established by culture, antibiotics should be changed, if necessary, to target the causative agent. Duration of antibiotics depends on the clinical response, infecting pathogen, and initial site of infection, with most courses lasting 7 to 14 days. Attention should also be directed to serum glucose control because maintenance of glucose at 80 to 110 mg/dL using intensive insulin therapy is associated with reduced mortality.

Table 96-5 Recommended Management of Sepsis Start resuscitation immediately in patients with hypotension or serum lactate >4 mmol/L. Obtain appropriate cultures before starting antibiotics, provided it does not significantly delay therapy. Evaluate for a focus of infection amenable to source control (e.g., abscess drainage). Remove intravascular catheters if potentially infected. Begin broad-spectrum antibiotics within the first hour of severe sepsis and septic shock. Fluid-resuscitate using crystalloids or colloids. Give fluid challenges of 1L of crystalloids or 300 to 500 mL of colloids over 30 minutes. Maintain mean arterial pressure ≥65 mm Hg. Use norepinephrine and dopamine centrally administered as vasopressors of choice. Use dobutamine in patients with myocardial dysfunction. Give red blood cells when hemoglobin decreases to 50%; late 7 mmol/L) Respiratory rate >30/min Blood pressure: RR diastolic 7 mmol/L (>19 mg/dL), respiration rate >30/min, blood pressure 65 years (Table 99-5). Patients with one or more of these factors may benefit from hospitalization; those with three or more are often best managed in an intensive care unit. Decisions based on these scores must be made also in the context of good clinical judgment. For persons in whom outpatient treatment for pneumonia is recommended, a “second look” reevaluation should be performed 24 to 48 hours after the initial examination to ensure that good progress is being made and hospitalization is not needed. Empirical antibiotic treatment without laboratory examination of sputum has been recommended for uncomplicated cases of community-acquired pneumonia, and in many instances a good sputum specimen is not readily provided by the patient. Nonetheless, in our view a pretreatment sputum examination helps guide management and is especially useful for review and guidance in instances of first treatment failure. Examination of respiratory secretions is especially valuable for prompt diagnosis and proper treatment of pneumonia in hospitalized patients or in outpatients with risk factors for infections with staphylococci or gram-negative rods; these risk factors include older age, recent hospitalizations, recent antibiotic therapy, underlying lung disease, or impairments of host defenses. The adequacy of a Gram-stained sputum specimen can be ascertained by

(1) the absence of squamous epithelial cells and (2) the presence of polymorphonuclear leukocytes (10 to 15 per highpower field). The presence of alveolar macrophages and bronchial epithelial cells confirms the lower respiratory tract origin of the specimen. The presence of a predominant organism, particularly if found within white blood cells in the absence of squamous cells, suggests that this is the likely pathogen. A specimen with many (>5 per high-power field) squamous epithelial cells is of no value for either culture or Gram stain, because it is contaminated with upper respiratory tract secretions. In some cases the patient cannot produce an adequate sputum sample despite vigorous attempts at sputum induction using an aerosolized solution of 3% hypertonic saline. The sicker the patient and the greater the likelihood of a multidrug-resistant pathogen, the more important it is to get an adequate sample of sputum for examination and culture. In cases of aspiration of mouth flora, a mixture of oral streptococci, gram-positive rods, and gram-negative organisms is found. In some cases, there may be inflammatory cells and no organisms seen on Gram stain. This finding suggests a number of possibilities, many of which are “nonbacterial” pneumonias (Table 99-6). Unless the diagnosis of acute bacterial pneumonia is clear, an acid-fast stain or fluorescent auramine-rhodamine stain of sputum for mycobacteria should be performed. If legionellosis is suspected, immunofluorescence stains for Legionella can be used, although the yield on expectorated sputum is low. The demonstration of elastin fibers in a potassium hydroxide preparation of sputum establishes a diagnosis of necrotizing pneumonia (Table 99-7). Blood cultures should be obtained and may be positive in as many as 20% to 30% of patients with bacterial pneumonia. Results of sputum cultures must be interpreted with caution, because pathogens causing pneumonia may fail to grow and sputum isolates may not be the pathogens responsible for infection. Careful screening of sputum specimens with Gram stain increases the accuracy of culture results. A tuberculin skin test or a blood test for interferon (IFN)-γ release in response to mycobacterial antigens should be applied in all cases of pneumonia of uncertain cause. A negative tuberculin test may occur despite active pulmonary and/ or disseminated tuberculosis.

Specific Pathogenic Organisms VIRAL AGENTS Respiratory viral infection is usually limited to the upper respiratory tract, and only a small proportion of infected adults develop pneumonia. In children, viruses are the most common cause of pneumonia, and respiratory syncytial virus is the most frequent organism. In adults, viruses are estimated to account only for a minority of pneumonias, and the influenza virus is the most common organism. Patients at increased risk for influenzal pneumonia include the aged; patients with chronic disease of the heart, lung, or kidney; and women in the last trimester of pregnancy. Cytomegalovirus may cause severe pneumonia in immunosuppressed patients, especially in organ transplant recipients. When varicella occurs in adults, some 10% to 20% develop pneu-

Chapter 99—Infections of the Lower Respiratory Tract

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Table 99-6 Sputum Gram Stain Showing Inflammatory Cells and No Organisms Possibilities Prior antibiotic treatment Viral pneumonia

Mycoplasma pneumoniae infection Legionella pneumophila infection Chlamydophila psittaci infection Chlamydophila pneumoniae infection Q fever

Clinical Setting

Confirmation of Diagnosis

Treatment

Winter months influenza, may be mild or life threatening

Serologic studies, virus culture, antigen detection

Oseltamivir or zanamivir for influenza A or B, ribavirin for respiratory syncytial virus

Hacking, nonproductive cough

Cold agglutinins, serologic studies

Doxycycline or macrolide

Chronic lung disease, hospital acquired, summer predominance Exposure to birds (e.g., parrots, turkeys) Hacking cough, sinusitis

DFA of sputum, bronchial brush biopsy, or pleural fluid, culture, serologic studies Serologic studies

Azithromycin or levofloxacin

Serologic studies, antigen detection

Tetracycline or macrolides

Exposure to cattle, South Africa

Serologic studies

Tetracycline or chloramphenicol

Tetracycline or doxycycline

DFA, direct immunofluorescence assay.

Table 99-7 Necrotizing Pneumonias Common Tuberculosis Staphylococcus Gram-negative bacilli Anaerobes Fungi Pneumocystis jirovecii Rare Streptococcus pneumoniae Legionella Viruses Mycoplasma pneumoniae

monia, which commonly leaves a pattern of diffuse punctate calcification on chest radiographs. Measles is occasionally complicated by pneumonia. Cases of pneumonia and adult respiratory distress syndrome caused by hantavirus have been reported, primarily among persons residing in the southwestern United States. This severe, rapidly progressive, and often fatal infection occurs largely among otherwise healthy young adults who have been exposed to rodent droppings. Treatment is supportive. Other viral pneumonias, of which influenza is the prototype in adults, typically occur in community epidemics and usually develop 1 to 2 days after the onset of flulike symptoms. Major features include a dry cough, dyspnea, generalized discomfort, unremarkable physical examination findings, and an interstitial pattern on the chest radiograph. Influenza-induced necrosis of respiratory epithelial cells predisposes to bacterial colonization. This may result in superimposed bacterial pneumonia, most often caused by S. pneumoniae, Staphylococcus aureus, or Haemophilus influenzae. A presumptive diagnosis may be made on the basis of the clinical presentation and the epidemiologic setting. Gram stain of sputum reveals inflammatory cells and rare bacteria. Detection of viral antigens in sputum can confirm the diagnosis rapidly. Viral isolation or serology also can establish the diagnosis, but not in time to guide management

decisions. Persons with laboratory-confirmed diagnosis of influenza B can benefit from treatment with the neuraminidase inhibitors oseltamivir or zanamivir for five days. If infection is caused by influenza A virus, zanamivir may be preferred or oseltamivir may be given together with rimantadine as influenza A viruses are increasingly resistant to oseltamivir. Treatment should be started within 48 hours of the onset of illness and is indicated for persons with influenza pneumonia or pneumonia complicated by bacterial superinfection and those who are very ill and at high risk for complications. Recently, highly pathogenic influenza virus strains (H5N1) emerging from avian reservoirs have caused mortality in more than 65% of infected persons in some southeast Asian nations. If and when recombination with currently circulating strains occurs, avian influenza could potentially cause another devastating influenza pandemic. In the spring and summer of 2009, a new H1N1 strain of influenza caused disease worldwide. Younger patients were at most risk. The strain produced a typical flu-like syndrome. Fatalities were noted predominantly in patients with underlying conditions. Other viral agents that may cause pneumonia in adults include parainfluenza virus, respiratory syncytial virus, adenovirus, and newly described viruses such as metapneumovirus. In 2003, pandemic spread of a newly identified corona virus (SARS-CoV) caused morbidity in more than 8000 persons around the globe with a mortality of nearly 10%. To date, no effective antiviral treatment is available. Seasonal outbreaks of this severe acute respiratory syndrome and other emerging viral respiratory infections, such as Nipah virus and Hendra virus infections, may be anticipated.

BACTERIAL AGENTS Streptococcus Pneumoniae The pneumococcus is still the most common bacterial cause of pneumonia in the community. The organism colonizes the oropharynx in up to 25% of healthy adults. An increased predisposition to pneumococcal pneumonia is seen in

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persons with sickle cell disease, prior splenectomy, chronic lung disease, hematologic malignancy, alcoholism, HIV infection, and renal failure. Clinical features include fever, rigors, chills, cough, respiratory distress, signs of pulmonary consolidation, confusion, and herpes labialis. By the second or third day of illness, the chest radiograph typically shows lobar consolidation with air bronchograms, but a patchy bronchopneumonic pattern may also be found. Abscess or cavitation rarely occurs. Sterile pleural effusions occur in up to 25% of cases, and empyema occurs in 1%. Typically, a leukocytosis of 15,000 to 30,000 cells/µL with neutrophilia is found, but leukopenia may be observed with fulminant infection, particularly among alcoholics and persons with HIV infection. Gram-positive cocci in pairs can be seen on microscopic examination of expectorated sputum samples in >60% of cases in patients with pneumococcal pneumonia. Positive blood cultures are found in 20% to 25% of patients. In most regions of the world, penicillin G remains the treatment of choice. In regions with a higher frequency of penicillin-resistant pneumococci, or in persons who are severely ill, cephalosporins or vancomycin may be indicated, depending on regional antibiotic sensitivity patterns.

Staphylococcus Aureus S. aureus infection accounts for 2% to 5% of communityacquired pneumonias, 11% of hospital-acquired pneumonias, and up to 26% of pneumonias after a viral infection. Persistent nasal colonization is observed in 15% to 30% of adults, and 90% of adults display intermittent colonization. Presentation is similar to that of pneumococcal pneumonia, but contrasting features include the development of parenchymal necrosis and abscess formation in up to 25% of patients and empyema in 10%. A hematogenous source of infection, such as septic thrombophlebitis, infective endocarditis, or an infected intravascular device, should be suspected in cases of staphylococcal pneumonia, particularly if the chest radiograph shows multiple or expanding nodular or wedge-shaped infiltrates. Early in staphylococcal pneumonia of hematogenous origin, sputum is rarely available. Blood cultures are usually positive, and associated skin lesions occur in 20% to 40% of cases. When sputum is available, Gram stain shows grapelike clusters of gram-positive cocci. S. aureus is recovered very easily from mixed culture samples, so its absence in a purulent specimen usually excludes it as a cause of the pneumonia. An increasing proportion of community acquired S. aureus strains in the United States is now methicillin resistant (MRSA). In affected regions, initial treatment with vancomycin or linezolid is recommended until sensitivity studies indicate that the isolate is sensitive to semisynthetic penicillins or cephalosporins.

Haemophilus Influenzae H. influenzae is a gram-negative coccobacillus often present in the upper respiratory tract, particularly among patients with chronic obstructive pulmonary disease. Its isolation from sputum in these patients is to be expected. Confirmation of its role in the pathogenesis of pneumonia depends on isolating the organism in the blood, pleural fluid, or lung tissue. Nevertheless, many cases of pneumonia caused by this organism will not be confirmed using these rigid criteria, and in a patient with pneumonia the demonstration

of gram-negative coccobacilli on Gram stain of sputum should prompt institution of treatment with ampicillin plus a β-lactamase inhibitor or a second- or third-generation cephalosporin.

Gram-Negative Bacilli Gram-negative bacilli have emerged as pathogens of major importance with the introduction of potent antibiotics and the proliferation of intensive care units. They are frequently encountered in patients with structural abnormalities of the tracheobronchial tree, such as chronic obstructive pulmonary disease and cystic fibrosis in the setting of neutropenia, alcoholism, diabetes mellitus, malignancy, and chronic disease of the heart and kidney. They are ubiquitous throughout the hospital, contaminating equipment and instruments, and are the major source of nosocomial pneumonia. Specific organisms have been associated with certain situations; for example, Klebsiella pneumoniae is particularly common in chronic alcoholics, Escherichia coli pneumonia is associated with bacteremias arising from the intestinal or urinary tract, and Pseudomonas species commonly infect the lungs of patients with cystic fibrosis. Precise etiologic diagnosis is confounded by the frequency with which these organisms colonize the upper airways in predisposed patients. Treatment of patients with Pseudomonas aeruginosa infection or seriously ill patients generally includes the use of two active agents, such as an extended spectrum penicillin, a carbapenem, or a third-generation cephalosporin plus a fluoroquinolone.

OTHER CAUSES OF ACUTE PNEUMONIA Mycoplasma Pneumoniae Not only is Mycoplasma pneumoniae a common cause of pneumonia in young adults, but it also produces a wide range of extrapulmonary features that may be the only findings. Fewer than 10% of infected patients develop symptoms of lower respiratory tract infection. Respiratory findings resemble those of viral pneumonia. Hacking, nonproductive cough is characteristic. Nonpulmonary features include myalgias, arthralgias, skin lesions (rashes, erythema nodosum and multiforme, or Stevens-Johnson syndrome), and neurologic complications (meningitis, encephalitis, transverse myelitis, cranial nerve, or peripheral neuritis). The occurrence of acute, multifocal neurologic abnormalities may be helpful in distinguishing Mycoplasma pneumonia from that caused by Chlamydia or Legionella. The neurologic abnormalities characteristically resolve completely as the acute illness subsides. In some patients, cold agglutinins may be seen at the bedside by observing red blood cell clumping on the walls of a glass tube containing anticoagulated blood incubated on ice for at least 10 minutes; they are also occasionally positive in other respiratory infections. Complement fixation antibody testing can suggest the diagnosis. Treatment for 7 to 14 days with doxycycline or a macrolide decreases the duration of symptoms and hastens radiographic resolution but does not eradicate the organism from the respiratory tract.

Chlamydophila (Chlamydia) Pneumoniae Five percent to 15% of cases of community-acquired pneumonia may be caused by Chlamydophila pneumoniae

Chapter 99—Infections of the Lower Respiratory Tract (formerly called the TWAR agent). Infection is spread presumably through the respiratory route, from person to person, and onset of disease is generally subacute, often manifested by pharyngitis, sinusitis, bronchitis, and pneumonia. The radiographic appearance of pneumonia caused by C. pneumoniae resembles that of Mycoplasma infection. Illness is relatively mild and often prolonged. Diagnosis of this infection is difficult and requires cultivation of the organism in special cell lines or testing of acute and convalescent sera for antibody levels. Although the organism is sensitive to macrolides and tetracyclines, treatment may have little effect on the course of disease.

Legionella Legionella are fastidious gram-negative bacilli that were responsible for respiratory infections long before the wellpublicized outbreak of legionnaires’ disease in 1976, which led to the recognition of this distinct disease entity and to the identification of the responsible bacillus. (The high mortality rate from this outbreak of a hitherto unrecognized disease among participants at an American Legion convention destroyed the reputation of one of Philadelphia’s finest hotels.) These organisms are distributed widely in water, and outbreaks have been related to their presence in water towers, air conditioners, condensers, potable water, and even hospital showerheads. Infection may occur sporadically or in outbreaks. Although healthy subjects can be affected, there is an increased risk in patients with chronic diseases of the heart, lungs, or kidneys; malignancy; and impairment of cell-mediated immunity. After an incubation period of 2 to 10 days, the illness usually begins gradually with a dry cough, respiratory distress, fever, rigors, malaise, weakness, headache, confusion, and gastrointestinal disturbance. The chest radiograph shows alveolar shadowing that may have a lobar or patchy distribution, with or without pleural effusions. Approximately half of patients have a mild disease course; in those with a more severe clinical course, the diagnosis is suggested clinically by the combination of a rapidly progressive pneumonia, dry cough, and multiorgan involvement. Microhematuria and a low serum sodium concentration are often present. Gram stain of sputum shows neutrophils and no organisms. Diagnosis can be made by the following four methods: • Indirect fluorescent antibody testing of serum is positive in 75% of patients, but up to 8 weeks is required for seroconversion. • Direct fluorescence antibody testing of respiratory secretions is technically demanding and has a specificity of 95%. Sensitivity of this method is low when using expectorated sputum but greater in specimens obtained from bronchoscopy or transtracheal aspirate. • Legionella antigen can be detected in urine with a sensitivity of 80% to 95% for Legionella pneumophila type 1. • The organism can be cultured on charcoal yeast extract medium (the laboratory must be informed), but up to 10 days is required for growth. Levofloxacin for 10 to 14 days or alternatively azithromycin for 7 to 10 days is effective therapy. Rifampin may be added in the gravely ill patient, but its value is unproven. Prompt treatment results in fourfold to fivefold reduction in

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mortality. Patients usually respond within 12 to 48 hours, and it is very unusual for fever, leukocytosis, and confusion to persist beyond 4 days of therapy.

COMMUNITY-ACQUIRED PNEUMONIA OF UNCERTAIN CAUSE Although it is important to make the best effort to obtain specimens, there are many instances in which, because of difficulty in obtaining adequate sputum specimens or lack of laboratory facilities, empirical treatment of acute community-acquired pneumonia may be necessary. In such instances, initial therapy should be guided by the patient risk factors, comorbidities, and the severity of illness (Table 99-8).

TUBERCULOSIS Approximately 25,000 new cases of tuberculosis occur in the United States each year, with a worldwide incidence of 7 to 10 million. In North America, a disproportionately high number of cases occurs among the foreign born, racial and ethnic minorities, and the poor. M. tuberculosis is transmitted by the respiratory route from an infected patient with pulmonary tuberculosis to a susceptible host. Primary infection may be documented by the development of a positive tuberculin skin test result or a positive blood test for IFN-γ release in response to mycobacterial antigens. Occasionally the patient develops sufficient symptoms of fever and nonproductive cough to visit a physician, and a chest radiograph is taken; patchy or lobular infiltrates are noted in the anterior segment of the upper lobes or in the middle or lower lobes, often with associated hilar adenopathy. Pleurisy with effusion is a less common manifestation of primary tuberculosis. Primary infection usually is self-limited, but hematogenous dissemination seeds multiple organs, and latent foci are established and become niduses for delayed reactivation. Overall, 5% to 10% of individuals with a positive tuberculin skin test result develop disease over their lifetime. Factors associated with progression to clinical disease are age (the periods of greatest biologic vulnerability to tuberculosis being infancy and old age); underlying diseases that depress the cellular immune response (see Chapter 109); diabetes mellitus, gastrectomy, silicosis, and sarcoidosis; and the interval since primary infection, with disease progression most likely in the first few years after infection. Anti–TNF-α therapy can lead to activation of latent tuberculosis infection. Early progression of infection to disease is known as progressive primary tuberculosis and may manifest as miliary tuberculosis, sometimes with meningitis, or as pulmonary disease of the apical and posterior segments of the upper lobes or lower lobe disease. Most commonly, tuberculosis represents delayed reactivation. Symptoms begin insidiously with night sweats or chills and fatigue; fever is noted by fewer than 50% of patients, and hemoptysis by fewer than 25%. Physical examination findings may be unremarkable, or dullness and crackles may be present in the upper lung fields, occasionally with amphoric breath sounds. The chest radiograph may show cavitary disease with infiltrates in the posterior segment of the upper lobes or apical segments of the lower lobes; however, the radiographic findings in pulmonary tuberculosis can be quite variable.

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Table 99-8 Empirical Therapy for Treatment of Community-Acquired Pneumonia Outpatient Treatment Previously healthy, no recent antibiotics Underlying comorbidities or recent (within 3 months) antibiotics or regions where macrolide-resistant Pneumococcus is prevalent Inpatient Treatment (Non-ICU) Inpatient Treatment (ICU)

Azithromycin, doxycycline Levofloxacin, moxifloxacin, or gemifloxacin, 750 mg bid

Levofloxacin, moxifloxacin, or gemifloxacin (750 mg bid) Or A β-lactam (e.g., penicillin, ampicillin) plus azithromycin or azithromycin Cefotaxime, ceftriaxone, or ampicillin-sulbactam plus either azithromycin or (levofloxacin, moxifloxacin, or gemifloxacin)

Special Considerations If Pseudomonas is a concern If cMRSA is a concern

Piperacillin-tazobactam, cefepime, imipenem, or meropenem Plus ciprofloxacin or levofloxacin, 15 mg/kg every 12 hrs Add vancomycin or linezolid, 600 mg IV or PO every 12 hrs Azithromycin, 500 mg daily (IV, PO) Doxycycline, 100 mg bid PO Ciprofloxacin, 750 mg bid PO, 400 mg bid IV; levofloxacin, 750 mg daily (IV, PO); moxifloxacin, 400 mg daily (IV, PO); gemifloxacin, 320 mg daily PO Ampicillin-sulbactam, 500 mg q8h IV Piperacillin-tazobactam, 3.375 g IV q6h Ceftazidime, 2 g IV q8h; cefepime, 2 gm IV q12h Meropenem, 1 g IV q8h, imipenem, 1 g IV q8h

Data from Mandell LA, Wunderink RG, Anzueto A, et al: Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(Suppl):S27-S72, 2007. cMRSA, community-acquired methicillin-resistant Staphylococcus aureus; IV, intravenously; PO, orally.

Extrapulmonary tuberculosis also reflects reactivation of latent foci and accounts for approximately 15% of cases. Miliary tuberculosis is discussed in Chapter 95, meningeal tuberculosis in Chapter 97, and tuberculosis of bones and joints in Chapter 104. The elderly and patients with diabetes mellitus are more likely to have lower lobe tuberculosis. Because of the growing proportion of elderly individuals in our society and the growing prevalence of HIV infection, “atypical” presentations of tuberculosis are increasingly common. In HIVinfected patients, involvement of the lower lobes is frequent and extrapulmonary tuberculosis, frequently involving lymph nodes, is almost as common as pulmonary involvement. Tuberculin skin tests are likely to be negative in patients with CD4+ T-cell counts 105 CFU/mL identifies bacteriuria. The diagnosis of bacteriuria is also established in both women and men from a single catheterized urine specimen (not from an indwelling catheter) with one bacterial species isolated at concentrations >102 CFU/mL. A hazard in interpreting results of urine culture is that if the sample is allowed to stand at room temperature for a few hours before being cultured, bacteria can multiply. This results in spuriously high bacterial counts. For this reason, urine for culture should not be obtained from a catheter bag. Specimens that are not plated immediately should be refrigerated. Biochemical tests to detect bacteriuria are not reliable when numbers of bacteria are low.

TREATMENT AND OUTCOME Asymptomatic bacteriuria has not been shown to be harmful in most adult populations. Antimicrobial treatment for asymptomatic bacteriuria is indicated only for pregnant women and for patients undergoing urologic instrumentation. These patients should be screened for asymptomatic bacteriuria and treated if test results are positive. Pyuria accompanying asymptomatic bacteriuria is not an indication for antimicrobial treatment. On the other hand, all symptomatic patients with UTI should be treated with antimicrobials. Although most women with lower UTIs are cured by a single dose of antibiotic, such as a double-strength trimethoprim-sulfamethoxazole (TMP/SMZ 160/800 mg) tablet, a 3-day (“short course”) treatment with ciprofloxacin 250 mg bid or TMP/SMZ 160/800 mg bid provides higher cure rates and is now generally recommended. (Note that in some regions, more than 20% of E. coli are resistant to TMP/ SMZ.) β-lactams are not recommended for short-course therapy because of suboptimal clinical and bacteriologic results compared with those of other agents. Short-course therapy is not recommended for women with a history of UTI caused by a resistant bacterium, when the duration of symptoms is >1 week, or for men. In these patients 7 to 10 days of treatment are recommended. Cultures and results of sensitivity testing confirm the diagnosis and ascertain if the antibiotic is active against the pathogen, but these tests are not advocated in persons with uncomplicated cystitis unless treatment fails. Because of the difficulty in clinical distinction between cystitis and upper urinary tract disease, some patients treated for cystitis may experience relapse because of unrecognized upper tract disease. Recurrent UTIs in males should always raise the suspicion for an anatomic alteration of the urinary tract. Occasionally, urine cultures obtained from a patient with symptoms of UTI and pyuria are reported as exhibiting “no growth” or “insignificant growth.” This situation has been labeled the “urethral syndrome.” Low numbers of bacteria (as few as 100/mL of urine) may produce such infections of the urinary tract. In other instances, the urethral syndrome may be caused by Chlamydia or Ureaplasma, which will not

grow on routine culture media. Thus, if a patient with the urethral syndrome has responded to antibiotics, the course should be completed; otherwise, if symptoms and pyuria persist, the patient should receive a 7- to 10-day course of tetracycline, which is active against Chlamydia and Ureaplasma. Other considerations for patients with lower urinary tract symptoms and no or “insignificant” growth on cultures of urine include vaginitis, herpes simplex infection, and gonococcal infection (Neisseria gonorrhoeae will not grow on routine media used for urine culture). A pelvic examination and culture for gonococci may be indicated in this setting if the patient is sexually active. Men with urethral discomfort and discharge should be evaluated for urethritis (see Chapter 107). Men with suprapubic pain, frequency, and urgency should be evaluated for cystitis, as discussed earlier. The presence of fever suggests that infection involves more than just the bladder. Young, otherwise healthy, febrile patients with UTI may be treated on an ambulatory basis with a fluoroquinolone for 2 weeks, provided that (1) their condition does not appear toxic, (2) they are able to take oral fluids and medications, (3) they have friends or family at home, (4) they have good provisions for follow-up, and (5) they have no potentially complicating features such as diabetes mellitus, history of renal stones, obstructive disease of the urinary tract, or sickle cell disease. In this setting, urine specimens should be sent for culture and antimicrobial susceptibility testing. Gram stain of urine in patients hospitalized for pyelonephritis will guide initial therapy. Initial therapy with TMP/SMZ for pyelonephritis can no longer be recommended in the United States because of high levels of resistance in E. coli and in other organisms that can cause urosepsis. In ill patients with community-acquired pyelonephritis, parenteral treatment of a Gram-negative rod infection should be initiated with either a fluoroquinolone, piperacillin-tazobactam, or a third-generation cephalosporin. An aminoglycoside may be added if drug resistance is suspected or if the patient is very ill. The aminoglycoside should be promptly discontinued if antibiotic sensitivity studies indicate that it is not essential. The finding of gram-positive cocci in chains suggests that enterococci are the pathogens. This infection should be treated, at least initially, with vancomycin plus an aminoglycoside, until antimicrobial drug susceptibility of the enterococci is known. Gram-positive cocci in clusters may indicate staphylococci. Staphylococcus saprophyticus is a likely agent in otherwise healthy women and is sensitive to most antibiotics used in the treatment of UTI. In the older patient, Staphylococcus aureus should be considered, and this infection should initially be treated with vancomycin or linezolid, as methicillin-resistant S. aureus is increasingly prevalent even in the community. When antimicrobial resistance testing indicates susceptibility to a penicillinase-resistant penicillin, such as nafcillin or a cephalosporin, the regimen should be adjusted. Gram-positive cocci in the urine may represent endocarditis with septic embolization to the kidney. Therapy should be simplified when reports of antimicrobial susceptibility are available. A repeat urine culture after 2 days of effective treatment should show sterilization or a marked decrease in the urinary bacterial count. If the patient fails to demonstrate some clinical improvement after 2 to 3 days of treatment, or if the clinical picture indicates sepsis

Chapter 105—Infections of the Urinary Tract and the patient has been febrile for more than 1 week, a complicating feature should be suspected. Intranephric or perinephric abscess or obstruction caused by a stone or an enlarged prostate may underlie this presentation. Ultra sonography is a good first diagnostic procedure in this setting. This will generally detect obstruction and collections of pus and will also detect stones greater than 3 mm in diameter. If ultrasonography is negative in this setting, computed tomography is indicated. Obstruction must be relieved and abscesses drained to result in cure. Computed tomography–guided percutaneous drainage is the procedure of choice whenever possible. All patients with complicated UTI should have repeat urine cultures 1 to 2 weeks after treatment is completed to check for relapse. If relapse occurs, the patient may have pyelonephritis, prostatitis, or neuropathic or structural disease of the urinary tract. If a 6-week course of antibiotics active against the bacterial isolate is not effective in eradicating infection, the possibility of structural abnormalities or prostatic infection should be investigated. Urologic evaluation should be performed for all men with UTI (except urethritis) because of the high frequency of correctable anatomic lesions in this population. Long-term antibiotic prophylaxis may benefit some persons who experience frequent UTI such as persons with obstructive uropathy or children with vesiculoureteral reflux. A single daily dose of nitrofurantoin 50 mg, TMP/ SMZ 40/200, or ciprofloxacin 100 mg may suffice to prevent recurrence. Some women have frequent reinfections related to sexual activity. Prompt voiding and a single dose of an active antibiotic, such as 100 mg nitrofurantoin, 80/400 mg TMP/SMZ, or 100 mg ciprofloxacin just after sexual contact can decrease the reinfection rate in these women. The occurrence of pyuria in the absence of bacterial growth on culture of urine (12 hours, and the first-void portion of the urine is collected for mycobacterial cultures. Genital masses, when present, should be biopsied for microbiologic and histopathologic examination.

Prostatitis Although prostatic fluid has antibacterial properties, the prostate can become infected, usually by direct invasion through the urethra. Symptoms of back or perineal pain and fever are common. Some patients have pain with ejaculation. Rectal examination usually shows a tender prostate. Patients with acute prostatitis generally have an abnormal urinary sediment and pathogenic bacteria in cultures of urine. Acute prostatitis may be caused by the gonococcus but is most often caused by gram-negative bacilli. Treatment is directed against the pathogen observed on Gram stain of urine and is generally effective. Therapy should be continued for a minimum of 4 weeks. Parenteral therapy is required rarely. Prostatic abscesses can be drained with ultrasound guidance. Chronic prostatitis may be asymptomatic and should be suspected in men with recurrent UTIs. The urine sediment may be relatively benign in patients with chronic bacterial prostatitis. In this instance, comparison of the first part of the urine sample, midstream urine, excretions expressed by massage of the prostate, and postmassage urine should reveal bacterial counts more than 10-fold greater in the prostatic secretions and postmassage urine samples than in first-void and midstream samples. Treatment of chronic bacterial prostatitis is hampered by poor penetration of the prostate by most antimicrobial agents. Long-term (6 to 12 weeks) treatment with a fluoroquinolone or TMP/SMZ is indicated and is effective in 60% to 70% of cases.

Prospectus for the Future • Better directed therapies to limit the spread of drug resistance • Better assays to identify low level bacterial infection in symptomatic patients

References Guay DR: Contemporary management of uncomplicated urinary tract infections. Drugs 68:1169-1205, 2008. Lutters M, Vogt-Ferrier NB: Antibiotic duration for treating uncomplicated, symptomatic lower urinary tract infections in elderly women. Cochrane Database Syst Rev 3:CD001535, 2008.

• Better treatment for chronic infection of the prostate

Nicolle LE, Bradley S, Colgan R, et al: Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 40:643-654, 2005. Pohl A: Modes of administration of antibiotics for symptomatic severe urinary tract infections. Cochrane Database Syst Rev 4:CD003237, 2007.

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106

Health Care–Associated Infections Amy J. Ray, Michelle V. Lisgaris, and Robert A. Salata

A

health care–associated or nosocomial infection is an infection that was not present or incubating at the time of admission to a health care facility. Although traditionally these infections have been described in the acute care setting, the proportion of such infections that occurs in long-term care and rehabilitation settings is increasing. Indeed, the risk of health care–associated infection (HAI) for such patient populations approaches that in the acute care setting. In most patients, infections appearing after 48 to 72 hours of hospitalization are considered to be nosocomially acquired. In the United States a patient admitted to a health care facility has a 5% to 10% chance of developing an HAI. These infections result in significant morbidity and mortality, with 2 million infections and nearly 100,000 deaths annually. The medical costs of HAIs in the United States are estimated to be approximately $10 billion per year. HAIs are unintended consequences of medical care. As with any infection, necessary elements for acquisition of infection are an infectious agent, a susceptible host, and a means of transmission. Pathogens in health care settings frequently include multidrug-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus, highly resistant gram-negative bacilli, and Clostridium difficile. The increasing drug resistance of many of these pathogens makes treatment challenging. With regard to the host, some factors associated with increased risk are not avoidable, such as advancing age, immunosuppression, and severity of illness. Contributing factors that can be minimized by thoughtful patient man agement include prolonged duration of hospitalization, the inappropriate use of antibiotics, the prolonged use of indwelling urinary and bloodstream catheters, and the failure of health care personnel to wash their hands. It is important to note that the most common means of transmission of health care–associated pathogens is via the hands of health care workers.

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Infection Control Surveillance of HAIs and the implementation of practices to prevent and control them are the responsibility of infectioncontrol personnel. Practices used to limit the spread of infection include isolating patients with potentially transmissible diseases (e.g., tuberculosis, influenza, MRSA infection), isolating patients at increased risk for acquiring infections (e.g., patients with neutropenia and cancer), and instituting mandatory hand washing and standard precautions with all patient contact. Standard precautions consider all blood and body fluids (e.g., cerebrospinal, amniotic, peritoneal, seminal, vaginal, blood-contaminated fluids) as potentially infectious. Gloves must be worn when exposure to these fluids is possible, especially with nonintact skin or mucosal surfaces. In addition, masks and gowns are worn when splashes are expected. Standard precautions are designed to reduce the risk of transmission of microorganism from both recognized and unrecognized sources of infection in hospitals and therefore must be used for every patient and every encounter.

Approach to the Hospitalized Patient with Possible Health Care– Associated Infection The development of an HAI is often heralded by a rise in temperature. The only sign of infection, particularly in the older or demented patient, may be a change in mental status (Table 106-1). Confusion or alterations in vital signs may be the only sign of serious underlying infection. Respiratory alkalosis or metabolic acidosis (caused by lactate accumulation), either with or without hypoxia, may be present.

Chapter 106—Health Care–Associated Infections Table 106-1 Signs of Infection in the Hospitalized Patient Fever or hypothermia Change in mental status Tachypnea and respiratory alkalosis Hypotension Oliguria Leukocytosis

When evaluating a patient with a new fever or possible infection, the physician should first assess the stability of the patient’s condition; hypotension, tachypnea, or new obtundation mandates rapid evaluation and treatment. The patient’s comorbidities, medications, recent procedures, and hospital course must be reviewed. The physician should elicit a history directed at possible causes of the fever, given that the patient often has a specific complaint that helps identify the source. Possible causes for nosocomial infections by anatomic site are listed in Web Table 106-1. Special attention should be given to examination of the skin for rash (e.g., drug eruption, ecthyma gangrenosum, disseminated candidiasis), wounds, or pressure sores; in addition, the physician must examine the sinuses (especially with nasogastric or nasotracheal tubes in place), mouth (for candidiasis or herpes infections), lungs (for pneumonia or thromboembolism), abdomen (e.g., for C. difficile–associated colitis, postoperative abscess, biliary sepsis), catheters, joints (for septic arthritis, gout, and pseudogout), and extremities (for deepvenous thrombosis). The patient’s medications should also be reviewed carefully for agents likely to produce fever (antibiotics and anticonvulsants especially). With drug fever, associated eosinophilia and/or rash is present in fewer than 25% of patients. Occasionally, a source of fever cannot be identified despite extensive evaluation. The classic definition of fever of unknown origin has recently been adapted to include the diagnosis of fever of unknown origin acquired nosocomially (see Chapter 95).

Catheter-Associated Urinary Tract Infections Urinary tract infections are the most common HAI and result in 900,000 additional hospitalization days at a cost well over $615 million annually. Approximately 80% of nosocomial urinary tract infections are associated with the use of indwelling urinary catheters, and up to 16% of all patients in a health care setting will have a urinary catheter during their stay. Fifteen percent of nosocomial bacteremias originate from the catheterized urinary tract, and some studies have shown increased mortality in patients with a catheter-associated urinary tract infection (CAUTI). Placement of an indwelling catheter into the urethra of a hospitalized patient facilitates access of pathogens to an ordinarily sterile site. Factors that predispose the patient to infection are shown in Table 106-2. The most common pathogens are enteric gram-negative rods; however, Candida and Enterococcus species are also important causes of infec-

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Table 106-2 Factors That Contribute to Nosocomial Urinary Tract Infection Indwelling catheters Extended duration of catheterization Open drainage (versus closed-bag drainage) Interruption of closed drainage system Use of broad-spectrum antibiotics (Candida)

tion. Prophylactic antibiotics, irrigation, urinary acidification, and use of antiseptics are of no value in preventing infection in this setting. Using indwelling catheters only when necessary can reduce CAUTI; studies have observed that 21% to 50% of all urinary catheters placed were for inappropriate indications. Urinary incontinence and routine fluid balance monitoring are not sufficient indications. Examples of situations in which catheterization is unavoidable may include the management of acute urinary retention or pressure wound healing in an incontinent patient. Thricedaily straight (in-and-out) catheterization, with the use of aseptic technique, is less likely to produce infection than use of indwelling catheters, and many patients with dysfunctional bladders have used this technique for years without developing significant urinary tract infections. If the use of an indwelling catheter is unavoidable, then the catheter drainage system should remain closed and unobstructed and kept securely fastened, with the collection bag remaining below the level of the bladder. The catheter should not be disconnected from the bag because specimens can be collected aseptically by inserting a needle through the distal catheter wall. Most important, the catheter should be removed as soon as possible. Additional strategies to reduce the incidence of urinary catheter–related infections have been the use of silver-coated or antibioticimpregnated catheters; several studies have been performed and show either conflicting results or benefit only in select populations, respectively. Therefore implementation of their use as routine practice has not been widely recommended. The clinical presentation of CAUTI is most commonly heralded by fever; localizing symptoms and signs may be absent in the catheterized patient. Microbiologic diagnosis usually requires the growth of at least 105 colony-forming units (CFU) of an organism per milliliter of a urine specimen collected aseptically from the catheter. Asymptomatic bacterial colonization of the catheterized bladder is highly prevalent and need not be treated. Candida infection of the bladder often resolves once broad-spectrum antibiotics are discontinued and the indwelling catheter has been removed. If Candida infection persists, then oral flu conazole or single-dose intravenous amphotericin B will often eradicate the organism, although recurrence rates are high and the long-term benefit of this approach has not been demonstrated. The best way to prevent CAUTI is to avoid catheterization unless absolutely necessary. For patients with indwelling urinary catheters, the most important risk factor of CAUTI is extended duration of catheterization; hence assessment for removal on a daily basis is encouraged.

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Nosocomial Pneumonia Pneumonia comprises 15% to 20% of all nosocomial infections, making it the second most frequent hospital-acquired infection. The vast majority of instances arise from aspiration of oropharyngeal contents. Aerobic gram-negative bacilli and often staphylococci, typically after the first 5 days of hospitalization, rapidly replace the normal oropharyngeal flora of the patient admitted to the hospital. The administration of broad-spectrum antibiotics, severe underlying illness (e.g., chronic lung disease), respiratory intubation, surgery, advanced age, and prolonged duration of hospitalization predispose individuals to colonization with these organisms. Sedation, loss of consciousness, and factors that depress gag and cough reflexes place the colonized patient at increased risk for aspiration and the development of pneumonia. The development of a new pulmonary infiltrate in a hospitalized patient may represent pneumonia, atelectasis, aspiration of gastric contents, drug reaction, or pulmonary infarction. If pneumonia is suggested, then prompt identification of the pathogen and appropriate treatment are critical because nosocomial pneumonia carries a 20% to 50% risk of mortality. If the patient cannot produce a sputum specimen adequate for interpretation (25 neutrophils per low-power [×100] field), then nasotracheal aspiration or bronchoscopic evaluation should be performed (see Chapter 99). Ventilator-associated pneumonia (VAP) accounts for up to 80% of nosocomially acquired respiratory infections; therefore the intubated patient in the intensive care unit should be monitored carefully for signs of pneumonia. Many patients are paralyzed to facilitate ventilator-dependent respiration. These patients have ineffective gag reflexes and often depressed cough as well and are therefore entirely dependent on suctioning to prevent aspiration. Patients whose airways are simply colonized but whose lower respiratory tracts are not infected should not be treated with antibiotics, despite positive sputum cultures. Premature treatment of colonization results in replacement of the initial colonists by more-resistant organisms, whereas delay in treatment of nosocomial pneumonia can result in death from overwhelming infection. The physician must therefore be able to accurately distinguish colonization from infection. The development of new fever, leukocytosis, pulmonary infiltrates, or deterioration of oxygenation suggests pneumonia rather than colonization. A Gram stain of sputum should be performed to identify the predominant organism or organisms, but initial antimicrobial therapy in these critically ill patients should include all likely pathogens because the high frequency of colonization makes interpretation of Gram stain results difficult. The use of clinical tools to assist in the distinction between colonization and infection, primarily in ventilated patients, is helpful in determining when antimicrobial treatment is needed (Fig. 106-1). The clinical pulmonary infection score (CPIS) assigns a numeric value to readily available clinical variables and assists in the determination of the presence of VAP. A CPIS of 6 has greater than 90% sensitivity in detecting pulmonary infection. Epidemics of nosocomial pneumonia are most often caused by transmission of pathogenic bacteria from the hands of medical personnel. The results of Gram stain and culture of the sputum and aspirate or the results of bronchoscopy specimens guide

Diagnostic Criterion

Results

Points

Temperature (°C)

≥ 36.5 and ≤ 38.4 ≥ 38.5 and ≤ 38.9 ≤ 36.0 and ≤ 39.0

0 1 2

≥ 4000 and ≤ 11,000 < 4000 or > 11,000 ≥ 500 band forms

0 1 1

Tracheal secretions

Absent Nonpurulent Purulent

0 1 2

PaO2/FiO2 (mm/Hg)

> 240 or ARDS ≤ 240 and no evidence of ARDs

0 2

Pulmonary radiographic findings

No infiltrate Diffuse or patchy infiltrate Localized infiltrate

0 1 2

No radiographic progression Radiographic progression after excluding CHF/ARDS

0 2

Leukocyte count (/µL)

Progression of pulmonary infiltrate Tracheal aspirate Gram stain and culture

No pathologic bacteria cultured 0 Pathologic bacteria cultured 1 Some pathologic bacteria on 1 Gram stain

Figure 106-1 With use of these diagnostic criteria, a clinical pulmonary infection score of 6 or greater has better than 90% sensitivity in detecting pulmonary infection.

antibiotic therapy. Gram-negative rods have been the predominant pathogens in this setting over the past three decades; these infections should be treated with a fluoro quinolone or aminoglycoside plus an extended-spectrum penicillin or cephalosporin until results of culture and sensitivity testing are known. Recent data from the National Nosocomial Infection Surveillance System indicate that S. aureus is the most common cause of nosocomial pneumonia in critically ill patients in the United States and that the prevalence of methicillin resistance is on the rise among these organisms. Therefore if gram-positive cocci in clusters are seen, then vancomycin or linezolid should be administered until sensitivities are known. A mixed flora suggestive of aspiration of oral anaerobes should prompt treatment with clindamycin or a penicillin–β-lactamase inhibitor combination. In certain hospitals, nosocomial pneumonia caused by Legionella species is a consideration, and if suggested, then a fluoroquinolone or macrolide should be included in the initial treatment regimen until specific testing can be performed. Selection of an appropriate antimicrobial agent is critical because initial treatment with an antibiotic to which the causative organism is not sensitive is associated with a greater than twofold increase in mortality. Patients with nosocomial pneumonia should also receive aggressive respiratory therapy to promote coughing and expectoration of secretions. Nosocomial pneumonias are best prevented in ventilated and nonventilated patients by (1) avoiding excessive sedation, (2) providing frequent suctioning and respiratory therapy, (3) positioning the patient in the semirecumbent

Chapter 106—Health Care–Associated Infections position, (4) weaning the patient from mechanical respiratory support as soon as possible, (5) initiating early enteral nutrition with avoidance of gastric overdistention, (6) encouraging frequent hand washing by all health care personnel, and (7) avoiding injudicious use of broad-spectrum or high-dose antibiotics. In addition, for ventilated patients orotracheal intubation is preferred because of increased risk of sinusitis and possibly VAP when nasogastric intubation is performed. The use of a cuffed endotracheal tube with in-line or subglottic suctioning is encouraged to manage secretions and prevent aspiration.

Intravascular Catheter– Related Bloodstream Infections More than 200,000 health care–associated bloodstream infections occur annually in the United States, the vast majority of which can be attributed to the presence of an intravascular catheter (catheter-related bloodstream infection [CRBSI]). Infections related to intravascular catheters may occur by means of bacteremic seeding or through infusion of contaminated material, but the vast majority of these infections occur through bacterial invasion at the site of catheter insertion. Catheters in frequent use today differ in their indications for use and their risk for CRBSI; therefore familiarization with appropriate selection may go a long way toward preventing CRBSI (Table 106-3; Web Fig. 106-1). Bacteria migrating through the catheter insertion site may colonize the catheter and then produce a septic phlebitis or bacteremia without evidence of local infection. Factors associated with a greater risk of intravenous CRBSI are shown in Table 106-4. Coagulase-negative staphylococci are the predominant pathogen in this setting, followed in equal frequency by S. aureus and enterococci. Candida species have now surpassed individual gram-negative rods as the third leading cause of CRBSI. The rising incidence of candidemia and enterococcal bacteremia is a reflection of the increasing proportion of immunocompromised and severely ill patients being admitted to acute care facilities. As a group, gramnegative enteric bacilli are the fourth most common cause of nosocomial bacteremia. Patients receiving parenteral nutrition are at particular risk for systemic infection with Candida species and gram-negative bacilli. If nosocomial bacteremia is suggested, then at least two sets of blood cultures should be obtained, one of which should be drawn from a peripheral vein and the other or others through the catheter of concern. Management of CRBSI varies according to the type of catheter involved and whether bacteremia-associated complications (e.g., septic thrombophlebitis, septic embolization, tunnel-site infection, endocarditis, osteomyelitis, metastatic seeding of bacteria) are present (see Table 106-3 and Web Fig. 106-1). A peripheral catheter (and all readily removable foreign bodies) should be replaced if bacteremia develops and no other primary site of infection is found. The catheter should also be removed if fever without an obvious source or if local phlebitis develops. Once the catheter has been removed, the site should be compressed in an attempt to express pus from

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the catheter entry site. If septic thrombophlebitis is documented, then surgical exploration may be required. The value of culturing a peripheral catheter tip is limited unless semiquantitative techniques are used (e.g., isolation of >15 CFU of bacteria by the roll plate method). Routine replacement of peripheral indwelling intravascular catheters every 72 hours decreases the risk of CRBSI. Central venous catheters are of the nontunneled, tunneled, or implanted device variety (Web Fig. 106-1). These catheters may be kept in place for prolonged periods with a lower infection risk than peripheral catheters. However, because they typically remain in place for prolonged periods of time, central venous catheters are associated with a greater overall rate of infection. Special microbiologic techniques can be employed to assist in the diagnosis of catheter-related bacteremia. When the diagnosis is confirmed, assessment for infection-related complications (e.g., port abscess, tunnel infection, endocarditis, septic thrombosis) should be performed to devise an appropriate management strategy. Consideration of catheter removal should be given with any nontunneled, central venous catheter–related bacteremia and is generally recommended. Removal of tunneled catheters or implanted devices is generally required when infectious complications occur. In situations in which the infected tunneled catheter or port cannot be removed, an antibiotic lock technique may be employed as an attempt to salvage the catheter. In cases of central venous catheter infections involving Candida species, other fungi, and S. aureus, attempts at catheter salvage have been largely unsuccessful. Prevention of central line–related bloodstream infection (CLBSI) can be accomplished by practicing an evidencebased approach that includes avoidance of the femoral site for catheterization, hand hygiene before insertion, and maximum sterile barriers including full drape and cap, sterile gown, and gloves for the inserter. In addition, chlorhexidine gluconate (concentration ≥0.5%) is the preferred antiseptic for skin preparation for patients at least 2 months of age as it broadly inhibits microbial growth with a prolonged residual effect. Antiseptic-coated catheters such as those coated with silver sulfadiazine may also reduce infection rates in the adult patient population. A simple checklist of these insertion interventions combined with catheter removal as soon as possible has been shown to significantly reduce rates of CLBSI.

Clostridium difficile Infection C. difficile infection (CDI) is the most clinically significant cause of hospital-acquired diarrheal disease and is often accompanied by fever and leukocytosis. It is a cause of significant morbidity and mortality and becoming increasingly difficult to control and eradicate. An epidemic strain of C. difficile associated with more severe disease, mortality, and frequent relapses has emerged in the United States, Canada, and Europe since 2003. C. difficile now rivals MRSA as the most common organism to cause HAIs in the United States. For full description of this important clinical condition, the reader is referred to Chapter 103.

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Table 106-3 Catheters Used for Vascular Access Catheter Type Peripheral Catheters Venous catheter (IV)

Entry Location

Size

Peripheral veins, usually of the forearm or the hand

72 hr for peripheral intravenous catheters Lower extremities and groin are at greater risk than upper extremities Cutdown presents a greater risk than percutaneous insertion Emergency insertion results in a greater risk than elective insertion Breakdown in skin integrity (e.g., burns) Insertion by physician is a greater risk than insertion by intravenous therapy teams

Surgical Site Infections Surgical site infections (SSIs) occur in up to 5% of the inpatient surgical population in the United States. These infec-

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tions increase length of hospital stay, are costly, and are associated with increased mortality. Infection at the surgical site usually occurs within the first 30 days postoperatively; however, in patients undergoing surgical placement of indwelling devices, surveillance for SSI continues up to 1 year postoperatively. The pathogenesis of these infections involves inoculation of skin bacteria at the time of the surgical incision. These infections can be classified as superficial, involving the skin and subcutaneous tissue; deep incisional, involving the fascia and muscles; or deep organ space. Prevention measures, such as minimizing preoperative length of stay, using nonirritative hair removal techniques, performing tight blood glucose control perioperatively, and using appropriate preoperative skin cleansing, are of great importance. If possible, preexisting infections must be treated before surgery to decrease the risk of bacterial seeding of the surgical site. Antibiotic therapy directed at staphylococci and streptococci, administered no later than 2 hours before the time of incision, markedly reduces but does not eliminate the risk of infection for select surgical procedures. Treatment of SSI should be directed by culture and may require débridement for cure.

Prospectus for the Future Antimicrobial-resistant bacteria (methicillin-resistant Staphylococcus aureus [MRSA], vancomycin-resistant enterococci, extended-spectrum β-lactamase [ESBL]–producing gram-negative bacilli), produced by injudicious use of broad-spectrum antimicrobial agents, will continue to offer greater challenges in the treatment of nosocomially acquired infections. With continued medical advances, such as organ and bone marrow transplantations, the emergence of additional opportunistic nosocomial pathogens will undoubtedly occur. In addition,

References American Thoracic Society, Infectious Disease Society of America: Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 162:505-511, 2005. Anderson DJ, Kaye KS, Classen D, et al: Strategies to prevent surgical site infections in acute care hospitals. Infect Control Hosp Epidemiol 29:S51-S61, 2008. Bartlett JG: Narrative review: The new epidemic of Clostridium difficile–associated enteric disease. Ann Intern Med 145:758-764, 2006. Lo E, Nicolle L, Classen D, et al: Strategies to prevent catheter-associated urinary tract infections in acute care hospitals. Infect Control Hosp Epidemiol 29:S41-S50, 2008.

monitoring and controlling infections in chronic care facilities will be increasingly important because of the emergence and transmission of antibiotic-resistant bacteria in this patient population and the risk of introducing these strains into the hospital environment. As medical professionals, we must share with infection-control practitioners the burden of recognizing individuals who are at risk for developing HAIs and instituting appropriate measures to prevent these infections.

Marschall J, Mermel LA, Classen D, et al: Strategies to prevent central line– associated bloodstream infections in acute care hospitals. Infect Control Hosp Epidemiol 29:S22-S30, 2008. Mermel LA, Allon M, Bouza E, et al: Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection. 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 49(1):1-45, 2009. Smith PW, Bennett G, Bradley S, et al: SHEA/APIC guideline: Infection prevention and control in the long-term care facility, July 2008. Infect Control Hosp Epidemiol 29:785-814, 2008.

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107

Sexually Transmitted Infections Corrilynn O. Hileman, Keith B. Armitage, and Robert A. Salata

S

exually transmitted infections (STIs) comprise a diverse group of infections caused by multiple microbial pathogens. These infections have common epidemiologic and clinical features. Since the mid 1980s, the field of STIs has evolved from one emphasizing the traditional venereal diseases of gonorrhea and syphilis to one concerned also with infections associated with Chlamydia trachomatis, herpes simplex virus (HSV), human papillomavirus (HPV), and human immunodeficiency virus (HIV). Changes in sexual attitudes and practices have contributed to a resurgence of some, but not all, venereal infections. For example, after a decline in primary and secondary syphilis in the 1990s, between 2000 and 2006 the incidence of syphilis increased. Concurrently, rates of syphilis infection in men who have sex with men (MSM) also increased, suggesting that this at-risk group may in part be reason for the trend. Indeed, 64% of primary and secondary syphilis cases in 2006 occurred in MSM. Chlamydia, the most commonly reported STI in the United States, with over a million cases reported in 2006, has been increasing in prevalence as well. Rates in women are increasing more than men and most in women aged 15 to 19. This likely represents increased screening efforts; however, it may also reflect the trend toward earlier sexual debut. At the outset, two common errors in approaching a patient with an STI should be avoided. The first error is failing to consider that an individual is at risk for an STI. All sexually active persons are at risk, not only because of their own sexual behavior, but because of their sexual partner’s behavior as well. Failure to consider risk factors often results in mistakes in diagnosis, inappropriate treatment, poor follow-up of infected sexual contacts, and, ultimately, recurrent or persistent infection. A second error with STIs is failing to recognize and diagnose co-infection. The most serious co-infection is with HIV. The worldwide epidemic of STIs fuels the global spread of HIV. STIs, most of which can be readily diagnosed and treated, may greatly enhance 998

the transmission of HIV infection. HIV, in turn, may alter the natural history of other STIs. This chapter divides STIs into broad groups according to whether major initial manifestations are (1) genital ulcers; (2) urethritis, cervicitis, and pelvic inflammatory disease (PID); (3) vaginitis; or (4) warts. All patients with an STI should be strongly encouraged to undergo screening for HIV infection and other concurrent STIs (see Chapter 108). Updated information on STIs can be found on the Centers for Disease Control and Prevention website at www.cdc.gov/std.

Genital Ulcer Disease Six infectious agents cause most genital ulcers (Table 107-1). The appearance of the lesions, natural history, and laboratory findings allow a clear-cut distinction among the possible causes in most instances. The two most common and significant infections in the United States are HSV-2 infection and syphilis.

HERPES SIMPLEX VIRUS INFECTION Genital herpes infection has reached epidemic proportions, causing a corresponding increase in public awareness and concern. Genital herpes differs from other STIs in its tendency for spontaneous recurrence. Its importance stems from the morbidity, both physical and psychological, of the recurrent genital lesions; the danger of transmission of a fulminant, often fatal, disease to newborns; and an association with transmission of HIV-1 infection.

Epidemiologic Factors HSV has a worldwide distribution. Humans are the only known reservoir of infection, which is spread by direct contact with infected secretions. Of the two types of HSV,

Incubation 9-50 days; at least one painless papule that gradually ulcerates; ulcers are large (1-4 cm), irregular, nontender, with thickened, rolled margins and beefy red tissue at base; older portions of ulcer show depigmented scarring, white; advancing edge contains new papules Characteristic large, soft, fleshy, cauliflower-like excrescences around vulva, glans, urethral orifice, anus, perineum

Granuloma inguinale, or donovanosis (rare in United States; caused by Klebsiella granulomatis)

None

None per se; association with cervical dysplasia or neoplasia

Metastatic infection of bones, joints, liver

Fever, arthritis, pericarditis, proctitis, meningoencephalitis, keratoconjunctivitis, preauricular adenopathy, edema of eyelids, erythema nodosum

Chief importance is distinction from syphilis and chancroid Rx: topical podophyllin ± cryosurgery, laser resection

Organism in Gram stain of pus; can be cultured on special media (75%); direct yields highest from lymph node Rx: azithromycin, 1 g PO once, ceftriaxone, 250 mg IM once, ciprofloxacin, 500 mg PO twice daily for 3 days, or erythromycin base, 500 mg PO 3 times daily for 7 days; sexual partners should be treated Test genital or lymph node specimens for C. trachomatis by culture, direct immunofluorescence, or nucleic acid detection; LGV CF positive 85%-90% (1-3 wk); must have high titer (>1 : 16), cross-reacts with other Chlamydia; also positive STS, rheumatoid factor, cryoglobulins Rx: surgical drainage may be required; doxycycline, 100 mg PO twice daily for 21 days Scraping or deep curetting at actively extending border; Wright or Giemsa stain reveals short, plump, bipolar staining; dark-staining Donovan bodies in macrophage vacuoles Rx: doxycycline, 100 mg PO twice daily for at least 21 days and until all lesions healed; may recur

Tzanck smear positive; tissue culture isolation, HSV-2 antigen; fourfold rise in antibodies to HSV-2 Rx: acyclovir, valacyclovir, or famciclovir for 7-10 days Tzanck smear positive; tissue culture positive; HSV-2 antigen; titers not helpful Rx: same as above, except shorter duration required Cannot be cultured; positive darkfield; VDRL test positive, 77%; FTA-abs positive, 86% (see Table 107-2) Rx: see Table 107-3

Diagnosis and Treatment

CF, complement fixation; FTA-abs, fluorescent treponemal antibody absorption; HSV, herpes simplex virus; IM, intramuscular; LGV, lymphogranuloma venereum; PO, orally; Rx, prescription; STS, serologic test for syphilis; VDRL, Venereal Disease Research Laboratory.

Condyloma acuminatum (genital warts; caused by human papillomavirus)

5-21 days after primary; one third bilateral, tender, matted iliac or femoral groove sign; multiple abscesses; coalescent, caseating, suppurative; thick yellow pus; sinus tracts; fistulas; strictures; genital ulcerations No true adenopathy; in one fifth, subcutaneous spread through lymphatics leads to indurated swelling or abscesses of groin (pseudobuboes)

Incubation 5-21 days; self-limited, painless papule, vesicle, or ulcer; lasts 2-3 days; noted in only 10%-40%

Lymphogranuloma venereum (600-1000 cases per year in United States; caused by Chlamydia trachomatis serovars L1, L2, L3)

None

Later stages

1 wk after chancre appears; bilateral or unilateral; firm, discrete, movable, no overlying skin changes, painless, nonsuppurative; may persist for months 1 wk after primary in 50%; painful, unilateral in two thirds; suppurative

Incubation 10-90 days (mean, 21) Chancre: painless papule that ulcerates with firm, raised border and smooth base; usually single; may be genital or almost anywhere; persists 3-6 wk, leaving thin, atrophic scar Incubation 3-5 days; vesicle or papule to pustule to ulcer; soft, not indurated; very painful

Primary syphilis (90,000 cases in United States per year; caused by Treponema pallidum)

Chancroid (2000 cases in United States per year; caused by Haemophilus ducreyi)

None

None

Grouped vesicles on erythematous base; painful; lasts 3-10 days

Fever

Systemic Features

Recurrent

Adenopathy

Tender, soft; often bilateral

Primary Lesion

Incubation 2-7 days; multiple painful vesicles on erythematous base; persists 7-14 days

Herpes genitalis (at least 50 million people have herpes genitalis in the United States; most caused by HSV-2) Primary

Disease

Table 107-1 Differentiation of Diseases Causing Genital Sores

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HSV-2 is the more frequent cause of genital infection. The major risk of infection is in the 14- to 29-year-old cohort and varies with sexual activity. Seroprevalence rates for HSV-2 infection are 22% in the general population and are as high as 40% to 50% in some North American populations. Many patients with serologic evidence of infection remain asymptomatic, and most transmission is thought to occur during periods of asymptomatic shedding of the virus.

Pathogenesis After exposure, HSV replicates within epithelial cells and lyses them, producing a thin-walled vesicle. Multinucleated cells are formed with characteristic intranuclear inclusions. Regional lymph nodes become enlarged and tender. HSV also migrates along sensory neurons to sensory ganglia, where it assumes a latent state. Exactly how viral reactivation occurs is uncertain. During reactivation, the virus appears to migrate back to skin along sensory nerves.

Clinical Presentation Genital lesions that develop 2 to 7 days after contact with infected secretions are the manifestation of the clinical illness. In men, painful vesicles usually appear on the glans or penile shaft; in women, they occur on the vulva, perineum, buttocks, cervix, or vagina. A vaginal discharge is frequently present. Primary infection is usually accompanied by inguinal adenopathy, fever, and malaise. Sacroradiculomyelitis or aseptic meningitis can complicate primary infection. Perianal and anal HSV-2 infections are especially common in MSM; tenesmus and rectal discharge often are the main complaints. The precipitating events associated with genital relapse of HSV infection are poorly understood. In individual cases, stress or menstruation may be implicated. Overall, genital recurrences develop in approximately 60% of patients infected with HSV. However, the frequency of asymptomatic cervical recurrence in women is not known. Many patients describe a characteristic prodrome of tingling or burning for 18 to 36 hours before the appearance of lesions. Recurrent HSV genital lesions are decreased in number, are usually stereotyped in location, are often restricted to the genital region, heal more quickly, and are associated with fewer systemic complaints. Recurrences are much higher and disease is more severe and prolonged in HIV co-infected patients; particularly those with advanced acquired immunodeficiency syndrome (AIDS).

Laboratory Diagnosis Although clinical features of HSV infection are suggestive diagnostically, these features are insensitive and not specific. Also, knowing the infection is caused by HSV-1 or -2 is helpful prognostically, as HSV-1 infections are less likely to recur and viral shedding is less. Diagnosis should be confirmed by laboratory testing. Isolation of HSV in cell culture is the gold standard for diagnosis, but sensitivity is low. Additional testing that may be performed includes Tzanck smear (66% sensitive) (see Chapter 93), Papanicolaou smear, immunofluorescent assay for viral antigen, and serologic testing. Direct antigen detection by means of an enzyme immunoassay test shows greater sensitivity than culture for later-stage HSV lesions and is equivalent to culture for earlystage infection. This is generally the diagnostic test of choice.

Serologic studies for HSV are generally useful only in the diagnosis of primary infection. Polymerase chain reaction (PCR) assays are available for the detection of HSV but are not currently approved by the U.S. Food and Drug Administration (FDA) for use on genital specimens.

Treatment Antiviral therapy for herpes genitalis has been shown to be beneficial and is the mainstay of management. Oral acyclovir, valacyclovir, and famciclovir have all been shown to be effective in treatment of symptomatic HSV infection. Treatment of both primary and recurrent episodes can partially control signs and symptoms of the infection if initiated early in the course. After primary infection, treatment can follow one of two strategies (i.e., episodic or chronic daily suppressive treatment). Chronic daily suppressive therapy has been shown to decrease the number of recurrences by 70% to 80% in those with six or more episodes per year. This strategy has also been shown to decrease transmission of HSV from those infected, although viral shedding may still occur. Despite the benefits of chronic daily therapy, acquired resistance to acyclovir has been seen occasionally in HIV-infected persons and in other immunocompromised hosts (e.g., after bone marrow transplantation). HSV most commonly becomes acyclovir resistant through a mutation in the thymidine kinase gene. Acyclovir-resistant HSV infection is commonly characterized by chronic, progressive mucocutaneous ulcers. In general, oral therapy is sufficient. It should be noted, however, that antiviral agents do not eradicate the latent stage of virus and do not affect the risk, frequency, or severity of recurrences once the medication is stopped. Hospitalization and administration of intravenous acyclovir are recommended for severe cases with fever, systemic symptoms, or extensive local or disseminated disease (e.g., pneumonia, meningitis, or hepatitis). The greatest risk of neonatal HSV infection occurs in pregnant women who acquire herpes genitalis near term. This risk is as high as 30% to 50%. However, in those women with a history of recurrent HSV or if primary HSV infection occurs during the first half of pregnancy, the risk of neonatal acquisition is low (i.e., 1 mo) Fungal Infection Candida esophagitis Cryptococcus neoformans meningitis Disseminated histoplasmosis Disseminated coccidioidomycosis Pneumocystis jirovecii pneumonia (PCP) Bacterial Infection Disseminated Mycobacterium avium-intracellulare Active Mycobacterium tuberculosis infection Recurrent Salmonella septicemia Recurrent bacterial pneumonia Viral Infection Chronic (>1 mo) mucocutaneous or esophageal herpes simplex virus infection Cytomegalovirus retinitis, esophagitis, or colitis Progressive multifocal leukoencephalopathy (JC virus)

Table 108-2 Other Conditions Fulfilling Clinical Criteria for AIDS Neoplasms Kaposi sarcoma High-grade, B-cell non-Hodgkin lymphoma Immunoblastic sarcoma Primary brain lymphoma Invasive carcinoma of the cervix Systemic Illness Human immunodeficiency virus (HIV) wasting syndrome (unintentional, unexplained loss of >10% of body weight)

Although the average lag period between initial infection by HIV and the clinical manifestations of severe immunodeficiency (AIDS) suggests that the introduction of the virus into North America may have occurred in the early 1970s, preserved specimens suggest that cases may have occurred in this part of the world as early as the 1960s. The Centers for Disease Control and Prevention (CDC) surveillance criteria for the diagnosis of AIDS, as modified in 1987, included a large number of OIs (Table 108-1) indicative of defects in cellular and/or humoral immunity, as well as certain neoplasms and other conditions associated with severe immunodeficiency (Table 108-2). The occurrence of any one of these conditions in an HIV-infected individual with no other cause of immunosuppression constituted the diagnosis of AIDS. In 1992 the CDC broadened the surveillance definition of AIDS to include all HIV-infected persons with severely depressed levels of cell-mediated immunity as indicated by CD4+ T-lymphocyte counts (CD4 counts) less than 200 cells/mm3. By 1993, AIDS had become the leading cause of death of American adults ages 25 to 44, a trend dramatically reversed by the introduction of highly active antiretroviral therapy (HAART) at the end of 1995 (Fig. 108-1). By the end of 2006, approximately 1.1 million persons in the United States were

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living with HIV and AIDS, and an estimated 56,300 persons became infected that year. Retrospective analysis of stored serum has revealed that HIV infection had been present in parts of Central Africa for decades before recognition of the clinical syndrome of AIDS. Since the early 1980s, HIV infection has become a major worldwide pandemic. HIV infection continues to spread, albeit at strikingly different rates, throughout all continents. Since the late 1990s, exceptionally rapid transmission has occurred throughout India, Southeast Asia, Southern Africa, the former Soviet Union, and some parts of Eastern Europe. Because of latency between HIV infection and the development of AIDS-associated illnesses, the clinically recognized epidemic of AIDS has lagged 6 to 8 years behind the spread of the virus into new populations. Although initially observed most frequently among homosexual men and intravenous drug users in the United States, heterosexual intercourse has been the dominant mode of HIV transmission throughout most of the world. The virus is present in semen and cervicovaginal secretions of infected individuals and can be transmitted by either partner during vaginal or anal intercourse. The concurrent presence of other sexually transmitted diseases (STDs), especially those associated with genital ulcerations, strongly facilitates sexual transmission of HIV-1 (see Chapter 107). In the United States, HIV infection has increased rapidly in women in the last decade; in several rural areas in the Southeast, women accounted for over one half of new cases in 2005. Over the past several years, there has also been a resurgence of HIV infection among young MSM. A disproportionate number of North American men and women infected by HIV are African American or Hispanic. Transmission by injection drug use (IDU) has been a major factor in this imbalance, given that IDU transmission has occurred most commonly in impoverished inner-city areas, where intravenous drug abuse is most prevalent. Differences in regional patterns of IDU have been a major factor in the greater than 100-fold regional variation in prevalence of AIDS cases in the United States. Since 2003, IDU transmission has significantly declined in the United States, whereas heterosexual transmission has continued to increase (Fig. 108-2). Vertical transmission of HIV from infected mother to child may occur in utero, during labor, or through breastfeeding. In the absence of antiretroviral treatment, HIV infects 25% to 30% of infants born to HIV-infected mothers. The rate of vertical transmission can be reduced to less than 2% by prenatal and perinatal treatment of the mother and postnatal treatment of the infant with effective antiretroviral drugs. HIV is almost always detectable in the blood of infected persons in the absence of effective antiretroviral therapy (ART). Before the nationwide implementation of a blood screening test in late 1985, infection by means of transfused blood or blood products accounted for nearly 3% of AIDS cases in the United States. Since 1985, all blood products in North America have been screened for HIV antigens and antibodies to HIV. The risk of transfusion-acquired HIV infection in North America and Western Europe is now exceedingly small, but not absent. HIV infection may occur after accidental parenteral exposures among health care workers. After injury by an

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Section XVII—Infectious Disease Trends in Annual Rates of Death due to the 9 Leading Causes among Persons 25–44 Years Old, USA, 1987–2002

Deaths per 100,000 population

40 35

Unintentional injury Cancer

30

Heart disease

25

Suicide

20

Homicide

15

HIV disease

10

Chronic liver

5

Stroke

0 1987

1989

1991

1993

1995

1997

1999

2001

Note: For comparison with data for 1999 and later years, data for 1987–1998 were modified to account for ICD-10 rules instead of ICD-9 rules.

Diabetes

Figure 108-1 Trends in annual death rates in persons ages 25 to 44, United States, 1987-2004. In 1993, AIDS became the leading cause of death of Americans in this age group. Since the widespread adoption of effective combination antiretroviral therapy in 1996, AIDS-related death rates have fallen sharply. By 1998, AIDS ranked fifth among the causes of death in this age group. (Data courtesy of Centers for Disease Control and Prevention.)

97.6 23.2 85.8

167.0 144.0 201.3

29.8 24.2

20.6 20.2

42.3 58.6 116.7 96.4

13.8 12.6 28.2 19.0

41.7 VT 41.2 71.6 50.7

43.3 47.6 151.4 101.5 55.1 76.1

52.0 53.4 73.3 67.6 131.1 175.2

48.7 60.0

21.8 32.6

48.3 44.1

70.4 73.7

237.0 461.3

157.9 84.0 73.3 149.2 70.8 41.4 44.8 74.5 99.0 70.6 148.2 127.4 106.9 156.8 114.4 99.2 127.6 122.1 179.7 88.1 181.9 176.9 138.8 215.2 132.7 83.1 196.9 227.9 206.1 298.8

NH 50.7 MA 159.0 RI 136.4 CT 242.3 NJ 204.0 243.5 DE 237.4 MD 298.4 DC 2060.9

110.7

HIV AIDS 2.5 2.5 American Samoa 46.6 30.4 Guam Rate = 137.0 Rate = 174.5a 7.5 4.6 Northern Mariana Islands 335.1 Puerto Rico 274.5 343.0 Virgin Islands, U.S. Figure 108-2 Estimated rates (per 100,000 population) for adults and adolescents living with HIV infection (not AIDS; 37 states and territories require confidential name-based HIV infection reporting) or with AIDS, United States and dependent areas (revised June 2007). AIDS rates show tremendous regional variation, from 2060 in the District of Columbia to 12 in Montana. (From Centers for Disease Control and Prevention: HIV/AIDS Surveillance Report, 2005. Vol 17, Rev ed. 2007.)

HIV-contaminated hollow needle, the risk of infection is approximately 0.3%. Observational data suggest that this risk can be reduced at least 10-fold by prompt postexposure prophylaxis.

Pathophysiology HIV is a member of the lentivirus family of retroviruses, which includes the agents of visna, equine infectious anemia

virus, and the SIVs. The core of HIV contains two singlestranded copies of the viral RNA genome, together with the virus-encoded enzymes reverse transcriptase, protease, and integrase (Fig. 108-3). Surrounding the structural (p24 and p18) proteins is a lipid bilayer derived from the host cell, through which protrude the transmembrane (gp41) and surface (gp120) envelope glycoproteins. The HIV envelope glycoproteins have a high affinity for the CD4 molecule on the surface of T-helper lymphocytes and other cells of monocyte-macrophage lineage. After HIV

Chapter 108—Human Immunodeficiency Virus Infection and AIDS

Retroviral particle

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Mature retroviral particle

Budding

Attachment

CD4

Cell membrame

Structural proteins

Chemokine receptor

Assembly

Cytoplasm

Penetration

Translation Regulatory proteins Two-LTR circular viral DNA

Uncoating

Unspliced mRNA

Linear unintegrated viral DNA

Reverse transcription

One-LTR circular viral DNA Preintegration complex

Transcription Integrated proviral DNA

Multiple spliced mRNAs

Nucleus

Figure 108-3 Essential steps in the life cycle of human immunodeficiency virus–1 (HIV-1). The first step is the attachment of the virus particle to the CD4 and chemokine (CCR5 or CXCR4) receptors on the surface of the lymphocyte (site of action of viral entry inhibitors; see text). The HIV-1 RNA genome then enters the cytoplasm as part of a nucleoprotein complex. The viral RNA genome is reverse-transcribed into a DNA duplex (site of action of reverse transcriptase inhibitors; see text). Once the viral DNA has been synthesized, the linear viral DNA molecule is incorporated into a preintegration complex that enters the nucleus. In the nucleus, unintegrated viral DNA is found in both linear and circular forms. The viral integrase (target for integrase inhibitors) catalyzes integration of the linear viral DNA into the host genome, where it remains for the life of the cell and serves as a template of viral transcription. Transcription of the integrated DNA template and alternative messenger RNA (mRNA) splicing creates spliced viral mRNA species encoding the viral accessory proteins, including Tat, Rev, and Nef, and the unspliced viral mRNA encoding the viral structural proteins, including the Gag-Pol precursor protein (cleaving of the precursor proteins is prevented by protease inhibitors; see text). A shift in the transcriptional pattern from the expression of predominantly multiply spliced viral mRNA to predominantly unspliced viral mRNA is indicative of active viral replication. All the viral transcripts are exported into the cytoplasm, where translation, assembly, and processing of the retroviral particle take place. The cycle is completed by the release of infectious retroviral particles from the cell. (Modified from Furtado MR, Callaway DS, Phair JP, et al: Persistence of HIV-1 transcription in patients receiving potent antiretroviral therapy. N Engl J Med 340:1614-1622, 1999, with permission.)

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binds to CD4, the envelope undergoes a conformational change that facilitates binding to another cellular coreceptor (the most important of these are the chemokine receptors CCR5 and CXCR4). This second binding event promotes a major conformational change that causes approximation of the viral and cellular membranes; fusion of these membranes is mediated by insertion of the newly exposed fusion domain of the envelope gp41 into the host cell membrane. As a result, the HIV nucleoprotein complex enters the cytoplasm, where the RNA viral genome undergoes reverse transcription by the virally encoded reverse transcriptase. The resulting double-stranded viral DNA enters the nucleus, where proper localization of the viral preintegration complex is mediated by host proteins, and integration of the DNA provirus into the host chromosome is catalyzed by the retroviral integrase (see Fig. 108-3). In some cells, after integration within the host genome the provirus may remain in a latent state for years, without detectable transcription of RNA or synthesis of viral protein. Latently infected resting memory CD4 lymphocytes serve as reservoirs of persistent infection for the life of infected patients even in the presence of effective ART (see later discussion). The bulk of viral replication takes place, however, in activated T cells, which are both more susceptible to HIV infection and more capable of supporting productive HIV replication. When a CD4 lymphocyte is activated (e.g., by recognition of antigenic peptides or by binding of proinflammatory cytokines), the viral promoter-enhancer region (the long terminal repeat) is activated to increase expression of HIV messenger RNA (mRNA). Virus-encoded regulatory proteins Tat and Rev facilitate mRNA expression and cytoplasmic transport, respectively. Core proteins, viral enzymes, and envelope proteins are encoded by the gag, pol, and env genes of HIV, respectively. Gag- and pol-encoded polypro teins are cleaved by viral proteases (see Fig. 108-3), whereas the envelope protein is cleaved and glycosylated by host proteases and glycosylases. Recent data indicate that more than 100 host proteins, in addition to the viral proteins, may be important for viral replication. Viral particles are assembled at the cell membrane, each containing two copies of unspliced mRNA within the core as the viral genome, and virions then are released from the cell by budding. Productive viral replication is lytic to infected T cells. A number of other host cells, including macrophages and certain dendritic cells, are also infected by HIV, but viral replication does not appear to be lytic to these cells.

IMMUNE DEFICIENCY IN HUMAN IMMUNODEFICIENCY VIRUS INFECTION Following HIV infection, high-level viral multiplication occurs in mucosal lymphoid tissues of the gut and in other lymphatic sites, and plasma HIV RNA levels (plasma viral load [PVL]) often exceed 1 million copies per milliliter during the second to fourth weeks after infection. Almost all instances of acute HIV infection are caused by R5 tropic viruses, viruses that use the chemokine receptor CCR5 for cellular entry. CD4+ T cells that express CCR5 are typically memory cells that are concentrated in mucosal tissues. In the first few weeks of infection, the memory CD4+ T-cell

Symptoms

Symptoms

Circulating CD4 lymphocytes

Viremia

Plasma HIV RNA

0 1 2 3 Months from infection

2

4 6 8 10 12 Years from infection

Figure 108-4 Natural history of HIV-1 infection in the untreated adult. Note the long period of clinical latency between the acute retroviral syndrome and AIDS-related disease. Note also the relative stability of the plasma HIV RNA level for several years after recovery from the initial burst of viremia, followed by an increase before the onset of AIDSrelated symptoms. (Modified from Shaw GW: Biology of human immunodeficiency viruses. Modified from Goldman L, Bennett JC [eds]: Cecil Textbook of Medicine, 21st ed. Philadelphia, WB Saunders, 2000, p 1896.)

population in the gut-associated lymphoid tissue (GALT) is profoundly depleted by the high-level cytopathic infection in these tissues. During subsequent weeks the PVL decreases, often rapidly. The decrease in viremia results largely from a partially effective, but incomplete, immune response. After 6 to 12 months, the PVL generally stabilizes at a level often called the viral “set point,” and may remain roughly at this level for several years (Fig. 108-4). The PVL at 6 to 12 months after infection is a significant predictor of the subsequent rate of progression of HIV disease but accounts for only half of the population variability in disease progression rates. Thus other factors likely contribute to the pace of disease progression. During the initial burst of viral replication shortly after infection, the majority of patients develop an acute retroviral syndrome (see discussion of sequential clinical manifestations of HIV-1 infection, later). After spontaneous recovery from the acute retroviral syndrome, the patient may feel entirely well for several years. During this period of clinical latency, however, high-level viral multiplication continues in multiple tissues. In the asymptomatic infected individual, over 100 billion new virions may be produced daily, while an equal number are removed from circulation. Rapid production and turnover of circulating CD4+ T-helper cells (CD4 cells) also occurs throughout the course of HIV infection. Although a highly dynamic and complex equilibrium between HIV and CD4 cells may be maintained for several years, a progressive decline in circulating CD4 cells occurs in the great majority of individuals; as disease progresses, a more dramatic CD4 cell decline is observed, following a sharp rise in PVL (see Fig. 108-4). HIV replication, with its attendant cell lysis, accounts only partially for this progres-

Chapter 108—Human Immunodeficiency Virus Infection and AIDS sive loss of CD4 cells. An ongoing state of cellular immune activation, not all of which can be attributed directly to HIV itself, appears to play a central role in this progressive immune deficiency. An HIV-specific immune response contributes to the decrease in the rate of viral replication during the initial weeks after acute HIV infection. During the years of clinical latency, virions are present in large numbers in the follicular dendritic processes of the germinal centers of the lymph nodes, which undergo both hyperplasia and progressive fibrosis. As HIV disease progresses over several years, the lymphatic tissue atrophies, and plasma viremia intensifies. In later-stage HIV disease, there is often persistent high-level viremia (see Fig. 108-4). The decline in the number of CD4 cells is accompanied by profound functional impairment of the remaining lymphocyte populations. Anergy may develop early in HIV infection and eventually occurs in virtually all persons with AIDS. With development of anergy, T-helper lymphocyte proliferation in response to antigenic stimuli is dramatically impaired. T-cell cytotoxic responses are diminished, and natural killer cell activity against virus-infected cells is greatly impaired, despite normal or increased numbers of these cells. Decrease in function as well as number of CD4 cells is central to the immune dysfunction, and this impairment partly underlies the failure of B-lymphocyte function, as measured by impaired capacity to synthesize antibody in response to new antigens. Profound impairment of multiple arms of the immune system underlies the enhanced risk of acquiring the OIs that are characteristic of AIDS.

INADEQUATE HOST DEFENSE MECHANISMS HIV continues to replicate despite brisk antibody responses to many components of the virus and demonstrable cellmediated immune responses to several HIV-derived proteins. There are several possible explanations for the inability of host responses to control HIV infection. The viral replication cycle allows integrated provirus to persist in the host genome in a transcriptionally latent state, in which it is not recognized by either humoral or cellular immune mechanisms (see Fig. 108-3). Conserved domains of the HIV envelope that are potential targets for neutralizing antibody are relatively inaccessible for generation of antibody responses, and extensive glycosylation of the viral envelope also hinders antibody formation and binding. Other conserved potential targets for antibody neutralization are typically unstable and manifest briefly only during the binding and fusion process. Envelope regions vary among different isolates, and although neutralizing antibody responses can be detected early after infection in most persons, mutational escape is readily and reproducibly demonstrable; errors in retroviral reverse transcription underlie this rapid escape from selection pressures and the resultant high degree of genetic variability among HIV isolates. Likewise, while CD8+ T-cell responses are key to control of retroviral replication in established infection, there is evidence of both CD8+ T-cell dysfunction and the emergence of escape mutations in sequences targeted by these cells. Preferential infection and deletion of

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HIV-specific CD4 T helper cells additionally hamper development of an effective anti-HIV immune response.

Diagnosis and Testing for Human Immunodeficiency Virus Infection Because HIV transmission is preventable, ART is effective, and prophylaxis against the major OIs can prevent these life-threatening events, it is important that routine testing for HIV infection be applied effectively. Testing should not be confined only to individuals at recognized high risk. Although not fully implemented nationwide yet, the current recommendation from the CDC is that HIV testing be considered a part of routine medical care, and that it be offered to all patients at the time of contact with the health care system without requirements for written consent or formal pretest and posttest counseling. Confidential pretest discussion is important to ensure that persons appreciate the importance and consequences of the test results. All individuals, regardless of the reason for their interaction with the health care system, should be counseled regarding safer sexual practices. Injection drug users should strongly be advised not to share needles. Positive test results should be given in a face-to-face meeting, during which the patient is given assurance that with adherence to current therapy he or she may live asymptomatically with HIV infection for decades. Arrangements for continuing medical care should be made at this time. All patients should be encouraged to notify their sexual partners and persons with whom they have shared needles. This is often difficult; regional health authorities may be of great assistance in confidential notification of persons at risk. All pregnant women should routinely be offered HIV testing, because ART will dramatically reduce mother-to-child transmission. Diagnosis of HIV infection is established by detection of antibodies to HIV in serum or in oral fluid and is confirmed by Western blot. These techniques are very sensitive in detecting HIV antibody, but individuals who have been infected recently may be antibody negative. During this “window period,” typically 1 to 2 weeks, infected persons have detectable HIV RNA and core p24 antigen in plasma. For recently exposed persons whose initial enzyme-linked immunosorbent assay (ELISA) result is negative, repeat ELISAs at 6 weeks and 3 months are indicated. False-positive ELISA results do occur because the HIV ELISA has been calibrated to achieve maximum sensitivity; all positive ELISA results must therefore be confirmed by Western blot reactivity with at least two different HIV proteins. In a person at high risk for HIV exposure, an indeterminate Western blot reaction pattern often represents early seroconversion; in such cases a positive plasma HIV RNA (>10,000 copies/mL) is indicative of acute HIV infection. Rapid and accessible testing methods play an increasingly important role in the diagnosis and confirmation of HIV infection. Oral fluid and/or urine testing are noninvasive approaches, and rapid test kits can provide tentative results within 30 minutes.

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Table 108-3 Acute HIV Retroviral Syndrome: Common Signs and Symptoms Sign or Symptom Fever Lymph node enlargement Sore throat Myalgia or arthralgia Rash Headache

Frequency (%) 98 75 70 60 50 35

Sequential Clinical Manifestations of Human Immunodeficiency Virus Type 1 Infection ACUTE HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND THE ACUTE RETROVIRAL SYNDROME Over 50% of HIV-infected persons experience a mono nucleosis-like syndrome (acute retroviral syndrome) 2 to 6 weeks after initial infection (see Fig. 108-4). Acute symptoms may include fever, sore throat, lymph node enlargement, rash, arthralgias, and headache and usually persist for several days to 3 weeks (Table 108-3). A maculopapular rash is common, is short-lived, and usually affects the trunk or face. Acute, self-limited aseptic meningitis, documented by cerebrospinal fluid (CSF) pleocytosis and isolation of HIV from CSF, is the most common clinical neurologic presentation and occurs in up to 10% of patients. The acute retroviral syndrome is sufficiently severe that a large proportion of patients seek medical attention. In the absence of a high index of suspicion, these symptoms are often mislabeled as an “acute viral syndrome.” This is especially unfortunate, because a very high plasma HIV RNA level during this period indicates a high likelihood of HIV transmission to sexual or needle-sharing partners, or from mother to infant. During the acute retroviral syndrome, HIV antibody is often not detectable, but HIV infection can be demonstrated by detection of HIV RNA or the HIV core p24 antigen in plasma. Within 4 to 12 weeks after HIV infection, specific antibodies develop that are directed against the three main gene products of HIV: gag, pol, and env.

ASYMPTOMATIC PHASE Untreated HIV infection usually results in a slow, nonlinear progression to severe immunodeficiency. Approximately 50% of untreated individuals develop AIDS within 10 years after HIV infection (see Fig. 108-4); an additional 30% have milder symptoms related to immunodeficiency, and less than 20% are entirely asymptomatic 10 years after infection. Progression of disease varies greatly among individuals. Adolescents with HIV progress to AIDS at a slower rate than older persons, and fewer than 30% develop AIDS within 10 years after HIV infection. The rate of progression of immunodeficiency is not influenced by the route of HIV transmission and, in the long term, does not appear to differ

by gender, although typically women with HIV infection tend to experience more rapid disease progression with lower levels of HIV in plasma. The majority of HIV-infected individuals are not diagnosed during the acute retroviral syndrome, are unaware of their infection, and are asymptomatic, often until their CD4 counts fall below 200 cells/mm3. Clinically recognized lymph node enlargement occurs in 35% to 40% of asymptomatic HIV-infected persons but is not significantly associated with either rate of progression of immunodeficiency or subsequent development of lymphoma. During early HIV infection, thrombocytopenia, probably caused by autoimmune platelet destruction, is common.

EARLY SYMPTOMATIC PHASE Mucocutaneous lesions may be the first manifestations of immune dysfunction, especially polydermatomal varicella-zoster infection (shingles), recurrent genital herpes simplex virus (HSV) infections, oral or vaginal candidiasis, or oral hairy leukoplakia (OHL). Patients with only mod erate immunodeficiency (CD4 counts between 200 and 500 cells/mm3) exhibit diminished antibody response to protein and polysaccharide antigens, as well as decreased cell-mediated immune function. These functional impairments are manifested clinically by a threefold to fourfold increase in incidence of bacteremic pneumonias caused by common pulmonary pathogens (especially Streptococcus pneumoniae and Haemophilus influenzae), as well as a marked increase in incidence of active pulmonary tuberculosis in endemic areas.

ADVANCED SYMPTOMATIC PHASE: OPPORTUNISTIC INFECTIONS With advanced immunodeficiency, indicated by CD4 counts below 200 cells/mm3, patients are at high risk for developing OIs (Table 108-4). For example, in the late 1980s, in the absence of specific prophylaxis and before the availability of effective antiretroviral drugs, 60% of HIV-infected North American men developed PCP. CD4 counts less than 50 cells/mm3 indicate profound immunosuppression and, in the absence of effective ART, are associated with a high mortality within the subsequent 12 to 24 months. Cytomegalovirus (CMV) retinitis, which can lead rapidly to blindness, and disseminated Mycobacterium avium-intracellulare (MAI) infections occur frequently. They respond adequately to specific therapy only when it is accompanied by effective control of viral replication.

SEX-SPECIFIC MANIFESTATIONS Several sex-specific manifestations are relevant to the management of HIV infection in women. Recognition of these manifestations is especially important because they are responsive to specific therapy; each manifestation may serve as the signal for HIV testing in a person with no prior clinical manifestations of immunodeficiency. • The earliest clinical manifestation of HIV infection in women may be frequent recurrence of Candida vaginitis in the absence of predisposing factors. Because recurrent

Chapter 108—Human Immunodeficiency Virus Infection and AIDS Table 108-4 Relation of CD4 Lymphocyte Counts to the Onset of Certain HIV-Associated Infections and Neoplasms in North America CD4 Count (cells/mm3)*

Opportunistic Infection or Neoplasm

>500 200-500

Herpes zoster, polydermatomal Mycobacterium tuberculosis infection Oral hairy leukoplakia Candida pharyngitis (thrush) Kaposi sarcoma, mucocutaneous (M) Bacterial pneumonia, recurrent Cervical neoplasia (F) Pneumocystis jirovecii pneumonia Histoplasmosis capsulatum infection, disseminated Kaposi sarcoma, visceral (M) Progressive multifocal leukoencephalopathy Lymphoma, non-Hodgkin Candida esophagitis Cytomegalovirus retinitis Mycobacterium avium-intracellulare, disseminated Toxoplasma gondii encephalitis Cryptosporidium parvum enteritis Cryptococcus neoformans meningitis Herpes simplex virus, chronic, ulcerative Cytomegalovirus esophagitis or colitis Lymphoma, central nervous system

100-200

140 min

< 140 min

Any positive: no treatment

History: Stroke or head trauma 90 d Surgery < 14 d History of cerebral hemorrhage BP > 185/110 Rapidly improving Hemorrhage < 21 d Seizures at onset Received anticoagulants < 48 hr

Any positive: no treatment

Standard laboratory values Severe anemia Platelets < 100,000 mL3 Protime > 15 sec Glu < 50 or > 400 mg/dL BP not easily reduced to < 175/100

Positive: no treatment

CT positive for blood or nonstroke disease

Total time > 180 min from onset

Total time < 180 min from onset

No rt-PA

rt-Pa IV 0.9 mg/kg max = 90 mg

Figure 124-7 Evaluating acute stroke for safe recombinant tissue-type plasminogen activator (rt-PA) therapy. BP, blood pressure; CT, computed tomography; Glu, glucose; IV, intravenous. (Data from National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581-1587, 1996.)

treatment is administered within the 3-hour window. There is increasing evidence that the benefit of thrombolysis exists up to 4.5 hours after symptom onset. Careful monitoring of blood pressure and avoidance of anticoagulants and antiplatelet agents are required for 24 hours after rt-PA administration. There is increasing evidence that intra-arterial thrombolysis is effective for acute stroke treatment up to 6 hours after stroke onset. A potential future development of thrombolytic therapy may be combination therapy with neuroprotective agents (such as glutamate antagonists and magnesium), which may extend the therapeutic time window beyond 3 hours. Use of platelet glycoprotein IIb/IIIa complex antagonists is also under study.

MANAGEMENT OF HYPERTENSION In the setting of an acute stroke, care must be taken regarding blood pressure control. Antihypertensive therapy is

1131

instituted if the blood pressure persistently exceeds 220 mm Hg systolic or 120 mm Hg diastolic (except in patients undergoing thrombolysis, in whom more stringent guidelines apply). Less marked elevations of blood pressure should not be treated acutely. Ideally an agent with a short half-life that can be easily titrated, such as intravenous labetalol, is used in the acute setting when necessary.

MANAGEMENT OF CEREBRAL EDEMA Only in large hemispheric infarction is ischemic cerebral edema sufficient to cause brain shift and transtentorial herniation. This is termed malignant MCA syndrome and usually results from infarction of the entire MCA territory in younger patients. If signs of herniation appear, airway intubation and mechanical hyperventilation produce transient cerebral vasoconstriction and may reduce ICP. Mannitol acts by reducing the volume of the surrounding unaffected brain, but its effects are also transient. Corticosteroids are of no benefit in cytotoxic edema. Decompressive hemicraniectomy has been shown to reduce mortality and increases the number of patients with a favorable functional outcome in patients with malignant MCA syndrome.

HYPERTENSIVE ENCEPHALOPATHY The term hypertensive encephalopathy refers to the diffuse cerebral effects of severe hypertension that are not caused by infarction or hemorrhage and that are potentially reversible with control of blood pressure. Patients experience headache, visual blurring (obscurations), confusion, and drowsiness. Seizures may develop. The blood pressure is typically very high (250/150 mm Hg), and papilledema and retinal hemorrhages are usually apparent on funduscopic examination. CT and MRI show diffuse cerebral edema with a predilection for the occipital lobes. A related disorder, reversible posterior leukoencephalopathy syndrome, has been described in hypertensive patients taking cyclosporin, tacrolimus, and erythropoietin. Hypertensive encephalopathy is a medical emergency. Treatment should be directed to the prompt but controlled lowering of blood pressure (e.g. with sodium nitroprusside), with care taken to avoid hypotension. The condition is clinically and pathophysiologically analogous to eclampsia.

REHABILITATION The majority of stroke-related deaths result from medical complications (e.g., pneumonia, myocardial infarction, sepsis) rather than the neurologic deficit. Admission to a specialist stroke unit improves functional outcome and reduces medical complications that follow stroke.

TREATMENT OF CEREBRAL VENOUS SINUS THROMBOSIS Acute anticoagulation with heparin is indicated for treatment of cerebral venous sinus thrombosis, even in the presence of hemorrhage. Interventional therapy with intrasinus rt-PA has been used in situations where the patient does not respond to anticoagulation. Warfarin is indicated

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Section XIX—Neurologic Disease

for prevention of recurrent cerebral venous sinus thrombosis; patients are usually treated for a minimum of 6 months.

SECONDARY PREVENTION OF ISCHEMIC STROKE Recent multicenter clinical trials have shown that aggressive control of stroke risk factors reduces the rate of recurrence. The use of cholesterol-lowering agents and angiotensinconverting enzyme inhibitors reduces the rate of stroke recurrence, even in normotensive patients.

Antiplatelet Therapy Prophylactic therapy with aspirin, with or without dipyridamole, or clopidogrel prevents recurrent events. Aspirin inhibits platelet aggregation by blocking platelet cyclooxygenase and thus prevents formation of thromboxane. Dipyridamole is a phosphodiesterase inhibitor that blocks uptake and metabolism of adenosine by vascular endothelial cells as well as potentiating the antiaggregating effects of prostacyclin. Clopidogrel inhibits ADP-induced platelet aggregation. All may be used for secondary stroke prevention. The addition of aspirin to clopidogrel does not confer added benefit for stroke prevention, as there is a significantly increased risk of hemorrhage.

Anticoagulation Warfarin is indicated for secondary stroke prevention in the setting of atrial fibrillation, in patients with severely reduced ejection fraction, and in those with valvular heart disease. Warfarin has not yet been proven any more effective than aspirin for secondary prevention of stroke in patients with PFO or intracranial ICA stenosis, although trials are ongoing.

Hypertension Hypertension is a well-recognized risk factor for ischemic and hemorrhagic stroke. A target blood pressure of less than 140/90 mm Hg is appropriate. Studies have indicated that the use of angiotensin-converting enzyme inhibitors in combination with a thiazide diuretic reduces the risk of stroke recurrence, even in normotensive patients.

Lipid-Lowering Agents There is evidence that treatment with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (“statins”) reduces stroke recurrence. This seems to be independent of their cholesterol-lowering effects and may result in part from upregulation of endothelial nitric oxide synthase and anti-inflammatory properties. All patients with TIA or stroke should be treated with a statin regardless of cholesterol level.

Table 124-6 Causes of Spontaneous Intracerebral Hemorrhage Intraparenchymal Hemorrhage Hypertension Amyloid (congophilic) angiopathy Arteriovenous malformation Bleeding diathesis Drugs (amphetamines, cocaine, anticoagulants, thrombolytics) Tumors Cerebral venous sinus thrombosis Hemorrhagic transformation of ischemic stroke Cerebral vasculitis Subarachnoid Hemorrhage Congenital saccular aneurysm (85%) Mycotic aneurysm Arteriovenous malformation Unknown (10%)

HYPERTENSIVE INTRACEREBRAL HEMORRHAGE Hypertensive ICH often occurs at the same sites that are affected in lacunar infarction. Pathologically, microaneurysms known as Charcot-Bouchard aneurysms have been identified in some patients. The most common sites for hypertensive hemorrhage are the putamen (40%), thalamus (12%), lobar white matter (15% to 20%), caudate (8%), pons (8%), and cerebellum (8%). Although CT readily identifies the hemorrhage, several clinical findings may help localize the site (Table 124-7). In general, severity of headache correlates with the size of the lesion. Diminished level of alertness is caused by mass effect, increased ICP, or direct involvement of the brainstem reticular-activating system. Seizures are slightly more frequent during the acute phase in ICH than in ischemic stroke. Both basal ganglia and thalamic hemorrhages may rupture into the adjacent ventricle and result in secondary hydrocephalus; cerebellar hemorrhage may cause obstructive hydrocephalus as a result of compression of the fourth ventricle. With intracerebral hematoma, the patient’s level of consciousness often deteriorates during the first 24 to 48 hours after the initial symptoms, usually because of the development of edema around the lesion or expansion of the hematoma. Edema that is sufficient to cause significant brain shift results in herniation of brain tissue. In addition to causing direct pressure on vital brainstem structures, herniation may cause compression of adjacent blood vessels (particularly the PCAs and ACAs), resulting in infarction.

LOBAR HEMORRHAGE

Intracerebral Hemorrhage ICH may be diffuse (subarachnoid hemorrhage) or focal (intraparenchymal) and accounts for 20% of all strokes. Table 124-6 lists the causes of spontaneous ICH. The acute rise in ICP from arterial rupture frequently results in loss of consciousness at the outset; some patients die from herniation.

Lobar hemorrhages occur in a peripheral distribution of the cerebral cortex. They are usually smaller than hypertensive ICHs and have a more benign prognosis. In young persons, lobar hemorrhages may be secondary to arteriovenous malformations or ingestion of sympathomimetic drugs. In elderly persons, they may occur because of congophilic amyloid angiopathy (CAA). The diagnosis of CAA is suggested by the finding of multiple microbleeds on gradient

Chapter 124—Cerebrovascular Disease

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Table 124-7 Clinical Manifestations Related to Site of Intracerebral Hemorrhage Site

Manifestation

Headache

Pupils

Eye Movements

Basal ganglia Thalamus

Severe Moderate

Pons

Severe

Normal Small, poorly reactive to light Small, reactive

Cerebellum

Severe, occipital

Normal

Normal Hyperconvergence Absent vertical gaze Horizontal gaze paresis Normal

Sensorimotor Signs

Other

Hemiparesis Hemisensory > motor loss Quadriplegia

Confusion, aphasia Hypersomnolence

Ataxia

Early vomiting

Coma

echo MRI. Patients with CAA often have associated dementia and seizures.

Anterior communicating artery

DIAGNOSIS, MANAGEMENT, AND PROGNOSIS

Middle cerebral artery

CT remains the diagnostic test of choice in the diagnosis of acute ICH, showing a hyperintense area with mass effect and (later) hypointense surrounding edema. MRI is less sensitive than CT for detecting hemorrhage in the early stages. The management of ICH depends on the size and location of the lesion. In the acute phase, the mass effect of a cerebral hematoma is far greater than in a large cerebral infarction, with a greater risk of herniation and death. In the chronic phase, however, the prognosis for recovery in patients who survive is much better for those with hemorrhage than for those with ischemic stroke. Therefore therapy for acute hemorrhage is directed at reducing mass effect either by medical decompression with controlled hyperventilation or mannitol or, in rare cases, by surgical decompression. This latter option should be considered urgently in cases of cerebellar hemorrhage in which patients are especially at risk of sudden deterioration either because of acute obstructive hydrocephalus (from compression of the fourth ventricle) or as a result of direct pressure on the caudal brainstem.

Intracranial Aneurysms Intracranial aneurysms occur in three forms: fusiform, mycotic, and saccular (congenital berry) aneurysms. Fusiform aneurysms represent ectatic dilations of large arteries, usually the basilar or intracranial carotid arteries. They rarely rupture but may compress adjacent brain tissue or cranial nerves and cause local neurologic dysfunction. Fusiform aneurysms are rarely accessible to surgical repair. Mycotic aneurysms occur in the context of bacterial endocarditis when septic emboli lodge in a peripheral vessel (see Chapter 100). They are often multiple and located distally in the arterial tree, and thus they are accessible to surgical repair should they fail to respond to antibiotic therapy. Saccular aneurysms form at arterial bifurcations (Fig. 124-8); 80% are located in the anterior circulation. They are thought to arise from a combination of a congenital defect in the arterial media and elastic lamina and gradual

Anterior cerebral artery Internal carotid artery Posterior communicating artery Posterior cerebral artery Superior cerebellar artery Paramedian arteries Circumferential artery Anterior inferior cerebellar artery Basilar artery Vertebral artery Posterior inferior cerebellar artery Anterior spinal artery Figure 124-8 The more common sites of berry aneurysms. The diagrammatic size of the aneurysm at the various sites is directly proportional to its frequency at that locus.

deterioration from hemodynamic stress. Their incidence is higher in patients with polycystic kidney disease and Marfan syndrome. Approximately 6% of the population harbors an unruptured saccular aneurysm; 25% of patients have multiple aneurysms. Fortunately, the annual incidence of rupture is only approximately 10 per 100,000. The risk of rupture is 1% per year. Of individuals with aneurysms that do rupture, 33% die before reaching a hospital, and another 20% die in the hospital. Overall, only 30% of patients recover without significant disability. Incidental aneurysms of the anterior circulation smaller than 7 mm have a very low risk of rupture (2.5 cm) may compress cranial nerves III, IV, and VI in the cavernous sinus. Aneurysms occasionally produce a TIA as a result of embolization from a thrombus within an aneurysm.

DIAGNOSIS CT of the brain shows subarachnoid hemorrhage in nearly all patients, and its location may suggest a site of rupture. A normal CT scan may not totally exclude subarachnoid hemorrhage and mandates a lumbar puncture in patients with suggestive symptoms. Care must be taken to centrifuge cerebrospinal fluid to detect true xanthochromia, the yellow coloration that develops by 6 hours after subarachnoid hemorrhage. Contrast CT or MRI identifies aneurysms larger than 5 mm as well as arteriovenous malformations. Cerebral angiography remains the gold standard for diagnosing intracranial aneurysms, and it is usually performed when surgery is being contemplated and deferred in severe cases in which significant risk of vasospasm exists. A small group of patients with predominantly peri-mesencephalic hemorrhage on CT have normal cerebral angiograms and a more benign outcome. The electrocardiogram may show deep, symmetrical T-wave inversion. Once the diagnosis of subarachnoid hemorrhage has been made (or if clinical suspicion persists, even with inconclusive testing), the patient should be managed under the guidance of a neurosurgical team.

MANAGEMENT AND PROGNOSIS An essential part of management of patients with subarachnoid hemorrhage is to prevent its complications (Table 124-8). To reduce the risk of rebleeding, patients are placed on bed rest with analgesics for pain relief, mild sedation, and the use of laxatives to reduce straining. Management of hypertension requires balancing the need to maintain a steady CPP in the context of raised ICP and possible vasospasm and, in contrast, the risk of rebleeding. Most rebleeding occurs within the first 3 days after rupture. The peak timing for vasospasm is between 5 and 9 days after the hemorrhage, and it may be accompanied by an alteration in the neurologic status. Oral nimodipine, a calcium channel blocker, should be given for 21 days after subarachnoid hemorrhage to prevent vasospasm.

Vascular Malformations Vascular malformations of the brain and spinal cord are grouped according to vessel size and composition. Venous angiomas are the most common and tend to lie close to the brain surface. Malformations composed of capillaries are called capillary telangiectases and are typically located within the brainstem. Cavernous angiomas are composed of dilated sinusoidal channels, are readily detectable on CT, and rarely bleed. Arteriovenous malformations are composed of tangles of arteries connected directly to veins without intervening capillaries. They may produce headache, seizures, or hemorrhage, accounting for 1% of all strokes. The initial hemorrhage typically occurs before the fourth decade, with a 7% risk of rebleeding within the first year afterward. Hemorrhage may occur into the brain parenchyma, subarachnoid space, or intraventricular space. Treatment of arteriovenous malformations is guided by individual factors, such as the age of the patient, location and composition of the lesion, and manifestations. As the natural history of unruptured arteriovenous malformations is unknown, treatment of asymptomatic patients is controversial. In general, arteriovenous malformations in older patients (>55 years) are treated conservatively, whereas younger patients are treated by surgical excision, embolization, or, less commonly, if small, by irradiation.

Chapter 124—Cerebrovascular Disease

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Prospectus for the Future The risk of both ischemic and hemorrhagic strokes can be reduced by vascular risk factor modification. Additional progress can be expected in this area, particularly in defining genetic factors that may increase stroke susceptibility. Important clinical trials are ongoing in the areas of treatment of PFO, warfarin in heart failure, and alternatives to warfarin for anticoagulation. Improved public recognition of stroke symptoms and better access to acute stroke units should result in

References Adams HP, del Zoppo G, Alberts MJ, et al: Guidelines for the early management of adults with ischemic stroke. Stroke 38:1655-1711, 2007. Friedlander RM: Arteriovenous malformations of the brain. N Engl J Med 356:2704-2712, 2007. Mant J, Hobbs F, Fletcher K, et al: Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial

greater use of thrombolysis and reduced morbidity from stroke. Trials of neuroprotective agents have been disappointing to date, although animal models were promising; research in this area is ongoing. Hemorrhagic stroke has been somewhat neglected in the past. The natural history of unruptured aneurysms and arteriovenous malformations is unknown, which makes treatment decisions difficult. These areas require further study.

Fibrillation Treatment of the Aged Study, BAFTA): A randomised controlled trial. Lancet 370:493-503, 2007. Wahlgren N, Ahmed N, Davalos A, et al: Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in StrokeMonitoring Study (SITS-MOST): An observational study. Lancet 369:275-282, 2007.

XIX

Chapter

125

Traumatic Brain Injury and Spinal Cord Injury Geoffrey S. F. Ling

T

raumatic brain injury (TBI) and traumatic spinal cord injury (TSCI) are leading causes of traumatic death and disability. Over 8 million patients undergo TBI each year, with approximately 52,000 patients in the United States dying as a direct consequence. An additional 11,000 patients are severely disabled by TSCI. The majority of TBIs and TSCIs are a result of falls, motor vehicle accidents, sportsrelated occurrences, and assaults. Among the almost 5.5 million TBI and TSCI survivors, most require prolonged rehabilitation.

Types of Traumatic Brain Injury Certain lesions necessitate neurosurgical intervention, whereas others do not. TBI conditions for which emergency neurosurgery is needed are penetrating wounds, intra cerebral hemorrhage with mass effect including subdural and epidural blood, bony injury such as displaced fracture, and vertebral subluxation. However, focal, hypoxic-anoxic, diffuse axonal, and diffuse microvascular injuries typically do not necessitate surgery.

Traumatic Brain Injury Management The initial goals in TBI care are the ABCs of airway, breathing, and circulation. Next is D for disability (neurologic). Every patient should undergo a detailed neurologic examination to ascertain the level of neurologic disability. An initial Glasgow Coma Score (GCS) should be assigned to each patient. The GCS (Table 125-1) categorizes TBI patients and provides a quantifiable measure of impairment. Patients with mild or moderate TBI typically recover quickly and fully. In the early stage of management, it is important to determine the duration of amnesia or loss 1136

of consciousness a patient may have experienced. The American Academy of Neurology Guideline uses a grading scale for concussion that is based primarily on the length of these intervals (Table 125-2). Longer periods of abnormal sensorium are associated with higher grades. Higher grades necessitate longer periods of convalescence. Other clinical guides that are used include the Cantu Grading System and the Colorado Medical Society Guidelines. In general, patients with mild or moderate TBI will not require major medical intervention, and almost all will do well after adequate convalescence. It is essential that patients have adequate recovery even from mild TBI. A subsequent head injury before full recovery may be catastrophic as it could result in “second impact syndrome” (SIS), which leads to worse clinical outcome including death. Severe TBI is defined as an injury that results in a GCS score of eight or less. This is a serious condition so to optimize outcome, medical management should adhere to currently accepted clinical guidelines such as the Brain Trauma Foundation “Clinical Guidelines for Severe TBI.” An important early intervention is airway protection, usually by endotracheal intubation. If elevated intracranial pressure (ICP) is suspected or if GCS < 8, the ICP should be monitored. Options for ICP monitoring are epidural fiberoptic catheter, subdural bolt, intraparenchymal fiberoptic catheter, or intraventricular catheter (IVC). All of these devices require drilling a small burr hole through the skull. The fiberoptic catheters are closed system devices and thus are associated with very low infection rates. However, measurements can drift after 5 days of use. As they cannot be zeroed, fiberoptic monitors are usually changed at this time. The subdural bolt can be zeroed but is associated with a slightly higher incidence of infection. The IVC or external drainage device is the most invasive as it requires inserting a catheter through brain parenchyma into a lateral cerebral ventricle. It can be zeroed and has the highest incidence of infection. The greatest benefit of the IVC is that it provides a therapeutic option in that CSF can be drained, which helps reduce intracranial volume and thus ICP.

Chapter 125—Traumatic Brain Injury and Spinal Cord Injury If there is elevated ICP, the patient’s head should be elevated to 30 degrees and kept midline, with a rigid neck collar used (until the cervical spine can be evaluated for stability). Mannitol should be given intravenously at a dose of 0.5 to 1.0 g/kg. Hyperventilation may also be used, with a goal of Pco2 of 34 to 36 mm Hg. ICP should be kept less than 20 mm Hg, with the cerebral perfusion pressure (CPP) greater than 60 mm Hg. CPP is the mathematical difference between mean arterial pressure (MAP) and ICP. Thus, CPP represents the arterial pressure that globally perfuses the brain. A head CT without contrast should be done as soon as possible both to identify lesions that will require surgery and to determine the extent of injury. If ICP remains poorly controlled, one can consider administering an intravenous bolus of 23% hypertonic saline (30 ml) followed by continuous infusion of 2% or 3% hypertonic saline (75 to 125 ml/hr) through a central venous catheter. If these interventions are unsuccessful, pharmacologic coma or surgical decompression should be considered. Pharmacologic coma can be induced with pentobarbital. This is given as a loading dose of 5 mg/kg, intravenously. Table 125-1 Glasgow Coma Score Best Eye Response

Best Verbal Response

Best Motor Response

1 = No eye opening 2 = Eye opening to pain 3 = Eye opening to verbal command 4 = Eyes open spontaneously

1 = No verbal response 2 = Incomprehensible sounds 3 = Inappropriate words

1 = No motor response 2 = Extension to pain 3 = Flexion to pain

4 = Confused

4 = Withdrawal from pain 5 = Localizing pain 6 = Obeys commands

5 = Oriented

Score = Eye Response + Verbal Response + Motor Response.

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followed by an infusion of 1 to 3 mg/kg/hr. Alternatively, propofol can be administered as a loading dose of 2 mg/kg intravenously, followed by an infusion of up to 200 mg/kg/ min. Continuous electroencephalographic (EEG) monitoring is helpful, as the limit of drug-induced coma is achieving ICP control or cerebral electrical burst-suppression. Persistently elevated ICP after all these efforts is ominous. Consideration should be made regarding frontal or temporal lobe decompression and hemicraniectomy. To meet CPP goals, patients must first be adequately hydrated. The goal of TBI fluid management is to increase the osmolar gradient between systemic vasculature and brain, not dehydration. For this purpose, hyperosmolar intravenous solutions, such as normal saline, are used. Other options are hypertonic saline (e.g., 3% sodium solutions). If meeting CPP goals is difficult with intravenous fluids alone, vasoactive pharmacologic agents such as norepinephrine and phenylephrine can be administered. These two agents are preferred because they are considered to have the least effect on cerebral vasomotor tone. Barbiturates and propofol are myocardial depressants, and therefore aggressive cardiovascular management entailing close cardiac monitoring and maintenance of euvolemia with appropriate fluid hydration and vasopressors as needed to maintain CPP will probably be necessary in the event of pharmacologic coma. Agitation can be treated with lorazepam or haloperidol. If these are inadequate, then infusions of midazolam or propofol may be used. Pain should be treated adequately. Acetaminophen and nonsteroidal anti-inflammatory agents may be adequate, but for moderate to severe pain, a narcotic analgesic such as fentanyl or morphine should be used. A benefit of opioids is that they can be reversed by naloxone, which allows reassessment of neurologic status. Hypoxia, seizures, and fever must be avoided. Maintaining Po2 at approximately 100 mm Hg is sufficient. Phenytoin is administered for the first 7 days after injury, as it reduces early onset seizures. After 7 days, this medication should be stopped. It can be restarted if late-onset seizures occur. Fever should be reduced with antipyretics such as acetaminophen, with cooling blankets used as needed. Other important

Table 125-2 American Academy of Neurology Concussion Management Grade 1 (Mild)

Grade 2 (Moderate)

Grade 3 (Severe)

Remove from duty, work, or play Examine immediately and at 5-min intervals May return to duty or work if clear within 15 min

Remove from duty for the rest of the day Examine frequently for signs of CNS deterioration Physician’s neurologic examination ASAP (within 24 hr) Return to duty after 1 full asymptomatic week (after being cleared by physician)

Take to emergency department Neurologic evaluation, including appropriate neuroimaging Consider hospital admission

Grade of Concussion

Return to Play or Work

Grade Grade Grade Grade Grade Grade Grade Grade

15 minutes 1 week 1 week 2 weeks 1 week 2 weeks 1 month Consult a neurologist

1 1 2 2 3 3 3 3

(first injury) (second injury) (first injury) (second injury) (first injury) (brief LOC) (first injury) (long LOC) (second injury) (third injury)

ASAP, as soon as possible; CNS, central nervous system; LOC, loss of consciousness.

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management considerations include prevention of gastric stress ulcers, deep vein thrombosis (DVT), and decubitus ulcer. Nutrition should be maintained, ideally with enteral feeds. However, if hyperosmolar therapy is used, then one should use concentrated enteral feeds that minimize free water content. After the first few hours have elapsed, efforts should be made to reduce hyperventilation. This therapy should be reserved only for initial emergency management. If the therapy is continued over 12 hours, metabolic compensation negates the ameliorative effects of respiratory alkalosis caused by a hypocapnic state. Regular neurologic examinations and continuous ICP and CPP measurements should be made. Generally, the peak period of cerebral edema is from 48 to 96 hours after TBI. Thereafter, this spontaneously resolves and clinical improvement should follow. A complication of TBI is “postconcussive syndrome.” The most common symptoms are headache, difficulty concentrating, appetite changes, sleep abnormalities, and irritability. Depending on the patient and the severity of TBI, postconcussive syndrome has a variable presentation and duration. In general, this condition lasts only a few weeks after injury. However, uncommonly, it can persist beyond a year or more. Therapies are focused on managing symptoms. For headache, nonsteroidal anti-inflammatory agents, migraine drugs, and biofeedback can be effective. For cognitive dysfunction, neuropsychologic testing may be helpful in determining appropriate intervention.

Traumatic Spinal Cord Injury Management The emergency management of traumatic injury to the spinal cord has improved with the measures recommended by the “Guidelines for the Management of Cervical Spine and Spinal Cord Injuries” from the American Association of Neurological Surgeons. As with TBI, therapy begins with the ABCs of airway, breathing, and circulation. For patients with high cervical lesions, spontaneous ventilation will be lost. Lesions lower than C5 may also be associated with insufficient ventilatory capability. If there is any concern that the airway or if ventilatory efforts are compromised, then emergency intubation is required. In a patient in whom the cervical spine has not been adequately imaged, the preferred method is nasotracheal intubation using fiberoptic guidance. Other approaches are nasotracheal (blind) or orotracheal intubation, but traction must be applied to maintain spinal column alignment. Maintaining adequate intravascular volume is of particular importance in the spinal cord–injured patient. Hypotension may result from either neurogenic shock or hypovolemia. For neurogenic shock, vasopressive pharmacologic agents such as phenylephrine may be needed. If tachycardia is present, then hypovolemia is the more likely cause, and fluid administration is the appropriate initial management. As with TBI, normal saline is the preferred fluid. After these issues have been addressed, a neurologic assessment should be made. An accompanying TBI needs to be considered. Up to 50% of TSCI patients have an associated

TBI. History with complete neurologic examination is the best method for diagnosis. Neuroimaging is often indicated for diagnostic evaluation, but not all patients need radiographic study. Normal neurologic history and examination findings in patients with a clear sensorium obviates the need for imaging studies. However, complaints of pain over the spine or of numbness, tingling, or weakness should raise the suspicion of spinal cord injury. In particular, a complaint of burning hands suggests cervical spinal cord injury. As accurately as possible, the time of injury should be recorded. A detailed neurologic examination is needed to identify the level of the injury and the completeness of any deficits and to document the degree of neurologic dysfunction at the earliest time possible. The level of the injury is the lowest spinal cord segment with intact motor and sensory function. The prognosis for neurologic improvement is better if the lesion is incomplete than if it is complete. During this acute period, serial examinations must be made frequently. If spinal cord injury is suspected, the patient should be immediately and appropriately immobilized, that is, with a rigid collar or back board or both. Radiologic evaluation should begin with plain x-ray films of the bony spine. Abnormalities on x-ray films should lead to further neuroimaging. Bony vertebrae should be examined with computed tomography (CT), and the spinal cord with magnetic resonance imaging (MRI). Intervertebral and paravertebral soft tissue are best studied with MRI. A chest radiograph should also be obtained in order to visualize the lower cervical and thoracic vertebrae. Presence of a pleural effusion in the setting of a possible thoracic spine injury suggests a hemothorax. If the C-spine radiograph is normal but the patient complains of neck pain, then ligamentous injury may be present. Ligamentous injury is evaluated by flexion-extension C-spine x-ray studies. However, in the acute period, pain may prevent an adequate study. Such patients should be kept in a rigid cervical collar for at least 24 to 48 hours until the pain and neck muscle spasm resolve. At that time, the study may be performed. If abnormal, the patient will need surgical evaluation. If spinal cord injury is identified, methylprednisolone should be given at an initial dose of 30 mg/kg intravenous bolus followed by a continuous infusion of 5.4 mg/kg/hr. The infusion should be for 23 hours if it is started within 3 hours of injury. If beyond 3 hours but still within 8 hours, then methylprednisolone should be given for 48 hours. The efficacy of methylprednisolone in TSCI from penetrating causes has not been demonstrated, so this therapy is reserved only for closed compartment injury. This is the only indication for steroid use in TSCI. At this time, the decision for surgical intervention should be made, based on the stability of the vertebral column.

SPINAL CORD SYNDROMES There are three main spinal cord syndromes: Brown-Séquard (hemisection), central cord, and anterior cord. Anterior cord syndrome is associated with deficits referable to bilateral anterior and lateral spinal cord columns. There is loss of touch, pain, and temperature sensations and motor function below the level of the lesion. The posterior column functions of proprioception and vibratory sensation remain intact. In Brown-Séquard syndrome, the deficits are caused by injury

Chapter 125—Traumatic Brain Injury and Spinal Cord Injury to a lateral half of the cord. There is functional loss of ipsilateral motor function, touch, proprioception, and vibration sensations, and contralateral pain and temperature sensations. Central cord or “man in a barrel” syndrome manifests as motor paralysis of both upper extremities while the lower extremities are spared. Weakness is greater proximally than distally. Pain and temperature sensations are generally reduced, but proprioception and vibration are spared.

SPINAL SHOCK After acute injury, spinal shock may occur, causing a temporary loss of spinal reflexes below the level of injury. Neurologic examination will reveal loss of deep tendon reflexes, bulbocavernosus reflex, and the anal wink. In high cervical injuries, the lower reflexes (bulbocavernosus and anal wink) may be preserved. There may also be the “SchiffSherrington” phenomenon, in which reflexes are affected above the level of injury. In addition, there will likely be loss of autonomic reflexes, leading to neurogenic shock, bowel ileus, and urinary retention.

OTHER TRAUMATIC SPINAL CORD INJURY MANAGEMENT ISSUES In the intensive care unit, the patient will need continued treatment. Once methylprednisolone therapy has been completed, there is no need for further steroid use. TSCI patients require close cardiovascular and ventilatory care. Other issues are genitourinary, bowel, infectious disease, nutrition, skin and prophylaxis against skin ulcers, and DVT formation. Patients with spinal cord injury are at risk for neurogenic shock and dysautonomia, which lead to peripheral vasodilation and hypotension. If the lesion is at T3 or above, then sympathetic tone to the heart is compromised. In this setting, hypotension is accompanied by bradycardia: the classic neurogenic shock triad of bradycardia, hypotension, and peripheral vasodilation. Therapy for dysautonomia begins by ensuring adequate circulating volume. The goal is to administer fluids to restore a euvolemic state. Blood should be transfused if the patient is anemic—that is, if the hematocrit is less than 30. If blood is not required, then either colloid (e.g., albumin solutions) or crystalloid (e.g., normal saline) may be used to maintain a central venous pressure (CVP) of 4 to 6 mm Hg. Hypervolemia should be avoided, as this will exacerbate peripheral edema. Once an adequate circulating volume has been achieved, a vasopressive agent such as phenylephrine, norepinephrine, or dopamine can be used. The goal MAP is 85 mm Hg or greater. Symptomatic bradycardia can be treated with atropine. Spinal cord patients are at risk for ventilatory compromise. Patients whose injuries are at C5 or higher typically require mechanical ventilation with an appropriate tidal volume (6 to 10 ml/kg) and Fio2 and mandatory machinedriven rate. The Fio2 should be set at a value that gives a Po2 of 80 to 100 mm Hg. The rate should be set to give a Pco2 of 40 mm Hg. Positive end-expiratory pressure (PEEP) should also be used to minimize atelectasis. If the patient does not show signs of ventilatory recovery within 2 weeks of intubation, a tracheostomy should be considered.

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Lesions below C5 may also be associated with inadequate spontaneous ventilation. Midcervical lesions may be associated with intact but compromised diaphragm function. If suspected, a “sniff ” test under fluoroscopy can be performed to determine if both hemidiaphragms are functioning properly. If not, intubation and tracheostomy with volume-controlled ventilation may be needed. If function is intact, then pressure support (PS) ventilation may be sufficient. The amount of PS to administer is dependent on patient requirements and should be sufficient to lead to an appropriate tidal volume. Fio2 and PEEP should be set as described previously. Patients with cervical lesions at C6 and below, including the thoracic cord, are generally not mechanical ventilator– dependent. However, their ventilatory effort may be inadequate, as the thoracic cord innervates intercostal muscles, which are accessory muscles of respiration. Such patients have decreased cough and inability to increase ventilation when needed. This leads to atelectasis and comprised ability to clear secretions, which may lead to pneumonia. These patients may benefit from chest physical therapy. Thromboembolic disease often complicates TSCI and is a leading cause of morbidity and mortality in these patients, as up to 80% will develop DVT without proper prophylaxis. Therefore all patients with TSCI should receive both anticoagulation and leg mechanical compression devices. As soon as possible, sequential compression devices (SCDs) or compression stockings should be placed on patients. Then, as soon as hemostasis is ensured, low–molecular-weight heparin (LMWH) should be initiated. Unfractionated heparin may also be used in conjunction with SCD, but LMWH is preferred. An inferior vena cava filter may be placed in those patients in whom anticoagulation therapy is contraindicated but should not be the primary means of preventing DVT. Mid to low thoracic spinal cord injury can lead to ileus. A nasogastric tube should be placed to decompress the stomach. Parenteral nutrition should be started as soon as possible. Enteral feeding should be delayed until gastrointestinal motility returns. This normally takes about 2 to 3 weeks. The pharmacologic agents metoclopramide, erythromycin, and cisapride may promote gastrointestinal motility. Gastric ulcer prophylaxis needs to be administered: H2receptor antagonists, proton pump inhibitors, antacids, or sucralfate. Pancreatitis and trauma-related perforated bowel are potential problems. Loss of abdominal muscle tone and visceral sensation may mask clinical signs such as pain, guarding, or rigidity. Bladder tone may be lost because of spinal shock. A Foley catheter should be placed and maintained for a minimum of 5 to 7 days to help drain the bladder and to evaluate circulatory volume and renal function. After spinal shock has resolved, autonomic dysreflexia may occur from bladder distention. Clinical signs such as sweating, skin flushing, and hypertension may be present. Clinical examination using palpation and percussion will reveal a distended bladder, which can be treated with bladder training or intermittent catheterization. Phenoxybenzamine may be helpful in this condition. Until enteral feeding can begin, parenteral nutrition should be used. A caloric level of 80% of the Harris-Benedict prediction, which approximates a patient’s total daily energy

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expenditures, should be used for quadriplegic patients. This is an approximation of a patient’s total daily energy expenditure and is based on the patient’s basal metabolic rate and activity level. The full Harris-Benedict predicted amount should be used for patients with thoracic spine injuries and below. There is a propensity for decubitus ulcers from pressure to develop in patients with TSCI. Mechanical kinetic beds, regular log rolling (every 2 hours), and padded orthotics are all useful in minimizing this complication. Orthotics, physical therapy, and occupational therapy (for cervical cord injury) are also important. Therapy should begin as soon as the spine is stabilized. This will serve to minimize contractures and to begin the rehabilitation process. It should be remembered that once therapy begins, energy expenditures will increase, and consequently additional nutrition will be needed. Also, as intermittent compression devices will need to be removed during therapy, the heparin dose may need to be increased.

Prognosis TRAUMATIC BRAIN INJURY The most useful prognostic indicator after TBI is the neurologic examination at presentation. Clearly, the better the neurologic examination findings, the higher the likelihood of improved recovery. The initial GCS is a very reliable

Table 125-3 American Spinal Injury Association Impairment Scale Grade

Injury Type

Definition

A

Complete

B C D E

Incomplete Incomplete Incomplete None

No motor or sensory function below the lesion Sensory but no motor function Some motor strength (3 Sensory and motor function normal

prognostic indicator. The lower the initial GCS, the less likely a patient will have meaningful neurologic or functional recovery.

TRAUMATIC SPINAL CORD INJURY For TSCI, the completeness of the injury is the most useful prognosticator. The American Spine Injury Association Impairment Scale grades spinal cord injury on the basis of completeness (Table 125-3). A grade A or complete motor and sensory deficit below the lesion is associated with the most ominous prognosis. If this status persists for longer than 24 hours, there is little reasonable likelihood of meaningful recovery. On the other hand, partial injuries, even severe, have substantial probability of recovery.

Prospectus for the Future Traumatic brain injury (TBI) and traumatic spinal cord injury (TSCI) prevention remains the most effective way of reducing the incidence of these disorders. Practice guidelines have contributed to improved outcome after TBI and TSCI. However, morbidity remains high. Medical management is largely confined to supportive efforts primarily directed toward minimizing secondary injury, optimizing perfusion and oxygenation, and preventing nonneurologic morbidity. Surgical intervention

References Belanger E, Levi AD: The acute and chronic management of spinal cord injury. J Am Coll Surg 190:603-618, 2000. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons: Guidelines for the management of severe traumatic brain injury. J Neurotrauma 24 (Suppl 1): S1-S106, 2007.

helps restore structural stability, minimize further injury, and reduce lesion size. However, neither medicine nor surgical treatment reverses neuronal death nor fully prevents secondary injury processes. Research is needed to improve our understanding of the pathogenesis of these injuries and find ways to mitigate it. As new pharmacologic, medical, and surgical approaches are introduced, there will be increasing opportunities to improve the still-poor prognosis of many patients.

Quality Standards Subcommittee, American Academy of Neurology: Practice parameter: The management of concussion in sports (summary statement). Neurology 48:581-585, 1997. Cushman JG, Agarwal N, Fabian TC, et al: Practice management guidelines for the management of mild traumatic brain injury: The EAST practice management guidelines work group. J Trauma 51:1016-1026, 2001. Hadley MN, Walters BC, Grabb PA, et al: Guidelines for the management of acute cervical spine and spinal cord injuries. Clin Neurosurg 49:407-498, 2002.

Chapter

126

XIX

Epilepsy Michel J. Berg

Definition Epileptic (or electrical) seizures are caused by abnormal highly synchronous discharges of neurons. They are a common sign of brain dysfunction. A wide variety of symptoms can occur depending on the location in the brain affected, including involuntary movements, sensations, and impaired consciousness. Seizures often occur during the course of medical or neurologic illnesses in which brain function is temporarily deranged (symptomatic seizures) (Table 126-1). The most common secondary causes are childhood febrile seizures, metabolic derangements (such as hypoglycemia or hyponatremia), intoxications (alcohol, cocaine), acute head traumas, and hypoxic-ischemic conditions (syncope, embolic stroke). Symptomatic seizures are usually self-limited, and recurrent seizures do not occur after the underlying disorder has been corrected. Therefore symptomatic seizures do not indicate epilepsy. Epilepsy is a chronic disorder defined as a condition with recurrent seizures not produced directly by a secondary cause. There are many different epileptic syndromes (the epilepsies). Classification of the epilepsy syndrome depends on a number of factors including the seizure type, cause, genetic factors, neuroimaging, and response to therapy. The phrase seizure disorder is synonymous with the word epilepsy. A single seizure may occur as an unprovoked event with no discoverable reason. By definition, two separate seizures are required to make the diagnosis of epilepsy; that is, a single seizure does not constitute epilepsy. Individuals with epilepsy have increased seizure susceptibility (lowered seizure threshold). Genetic factors and prior brain injury (from a multitude of causes) are the major contributors to such susceptibility. Most seizures in someone with epilepsy occur in an unpredictable fashion. It is this unpredictable timing that results in the major negative impact on quality of life. If functionally impairing seizures occur during waking hours (diurnal seizures), then activity restrictions are required including restriction from driving, operating heavy machin-

ery, heights, and unobserved swimming or bathing (showering with a good drain is recommended). These activity restrictions lead to loss of independence. The psychological impact of having intermittent involuntary loss of body control and the dependant status imposed by the activity restrictions are major contributors to the substantial increased incidence of comorbid depression in people with epilepsy (up to 50%). In many people with epilepsy there is a higher seizure frequency during sleep because of increased synchronization of neuronal activity. Seizures that occur exclusively in sleep constitute nocturnal epilepsy. In women with epilepsy (WWE), seizures sometimes occur more often during the week around menses or at ovulation (catamenial epilepsy). Sleep deprivation, alcohol consumption, infectious illness, certain medications, and severe emotional stressors can further lower the seizure threshold and are associated with more seizures in people with epilepsy (see Table 126-1).

Incidence and Etiology Seizures can occur at any time. Ten percent of people in developed countries have a seizure at some time during their lives. In contrast, 0.7% to 1% have current epilepsy (prevalence), and 3% to 4% have epilepsy at some time during their lives (lifetime prevalence). In the United States, there are approximately 125,000 new cases of epilepsy diagnosed each year (incidence). The incidence and prevalence are biphasic, with epilepsy being more common in childhood (primarily resulting from perinatal injury, infections, and genetic factors) and in old age (from stroke, tumors, and dementia) (Fig. 126-1). In developing countries the frequency of epilepsy is higher because of a variety of factors including increased brain infections with organisms such as cysticercosis. Before the 1990s, in most people with epilepsy the cause was not determined. The advent of magnetic resonance imaging (MRI) and, more recently, genetic analysis has substantially improved our ability to identify the underlying cause of many types of epilepsy. About 70% of adults and 1141

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Table 126-1 Causes of Symptomatic Seizures* Acute electrolyte/metabolic disorders Acute hyponatremia (155 mEq/L) Hyperosmolality (>310 mOsm/L) Hypocalcemia (50, Lyme disease, HIV-associated disease, or a paraneoplastic process must be considered. Electrodiagnostic studies consisting of nerve conduction testing and EMG can be a helpful extension of the physical examination. These studies are useful in defining whether the neuropathic process is caused by a primarily axonal or demyelinating process. In general, axonal degeneration decreases the amplitude of the CMAP out of proportion to the degree of reduction in peripheral nerve conduction velocity, whereas demyelination produces prominent reduction in conduction velocities. Nerve conduction testing can help determine, in the case of a demyelinating neuropathy, whether the process has an acquired or hereditary cause.

Table 130-12 Symptomatic Treatment for Neuropathic Pain Tricyclic Antidepressants Amitriptyline 10-150 mg qhs Nortriptyline 10-150 mg qhs Imipramine 10-150 mg qhs Desipramine 10-150 mg qhs Anticonvulsants Lamotrigine 200-400 mg qd Gabapentin 300-1200 mg tid Carbamazepine 100-200 mg tid Topiramate 150-200 mg bid Oxcarbazepine 1200-2400 mg qd Pregabalin 150-600 mg qd Alternative Treatments Tramadol 50-100 mg qid Mexiletine 150 mg bid-tid Lidoderm patches Capsaicin cream Transcutaneous nerve stimulation Acupuncture

A uniform slowing of nerve conduction usually suggests a hereditary cause. Electrodiagnostic studies can identify subclinical neuropathy (in patients receiving potentially neurotoxic medications) and can quantitate the extent of axon loss. Finally, these studies can localize the lesion in the case of radiculopathies, plexopathies, and multiple mononeuropathies. Sensory nerve biopsies are necessary in the diagnosis of a vasculitic neuropathy because treatment involves potentially toxic medications. Performing a muscle biopsy in addition to the nerve biopsy may improve the diagnostic yield and should be considered because the inflammation is random and focal and easily missed. Nerve biopsies are not indicated in “cryptogenic” neuropathies, diabetic neuropathy, or motor neuron disease.

Treatment Strategies in Peripheral Neuropathy Despite a very thorough history, examination, and laboratory studies, as many as one third of patients remain undiagnosed. In this situation, the focus of management is pain control. Patients with neuropathy frequently report a burning, searing, and aching sensation in their feet and hands that interferes with sleep. Neuropathic pain is difficult to treat but may respond to various medications having different mechanisms of action (Table 130-12). It is important to “start low and taper slow” and to treat for a minimum of 4 weeks before concluding that an agent is ineffective.

Common Mononeuropathies (see Table 130-7)

CARPAL TUNNEL SYNDROME Carpal tunnel syndrome results from compression of the median nerve at the wrist as it passes beneath the flexor

Chapter 130—Neuromuscular Diseases retinaculum. Symptoms usually begin in the dominant hand but commonly involve both hands over time. Patients typically report numbness, tingling, and burning sensations in the palm and in the fingers supplied by the median nerve: the thumb, index finger, middle finger, and medial one half of the ring finger. Some patients report that all fingers become numb. Pain and paresthesias are most prominent at night and often interrupt sleep. The pain is prominent at the wrist but may radiate to the forearm and occasionally to the shoulder. Shaking the hand relieves both pain and paresthesias. Percussion of the median nerve at the wrist provokes paresthesias in a median nerve distribution in 60% of patients (Tinel sign), and flexion of the wrist for 30 to 60 seconds provokes pain or paresthesias in 75% of cases (Phalen sign). Precipitating factors include activities that require repetitive wrist movements: mechanical work, gardening, house painting, and typing. Predisposing causes include pregnancy, diabetes, acromegaly, rheumatoid arthritis, chronic renal failure, thyroid disorders, and primary amyloidosis. The diagnosis is based on clinical symptoms and signs. Electrodiagnostic studies may demonstrate prolongation of the sensory or motor latencies across the wrist in up to 85% of patients. In more severe cases, EMG may demonstrate evidence of denervation in the abductor pollicis brevis. Treatment initially includes avoidance of repetitive wrist activities and the use of a neutral wrist splint. If these conservative measures fail, injections of lidocaine and methylprednisolone can be given into the carpal tunnel or surgical treatment by section of the transverse carpal ligament can effectively decompress the nerve. Indicators that have been shown to predict failure with conservative management include age >50, disease duration >10 months, constant paresthesias, and a positive Phalen sign in distal lower extremity weakness that progresses over a period of months. The onset is invariably

unilateral, but the condition may progress to involve both lower extremities. Physical therapy and effective pain management are essential; treatment with immune modulators is controversial.

TOXIC-INDUCED NEUROPATHIES Toxic neuropathies constitute a large number of disorders caused by alcohol, drugs, heavy metals, and environmental substances (Web Table 130-3). The majority of toxic neuropathies manifest as a distal sensorimotor axonal neuropathy that chronically progresses over time unless the offending agent is eliminated. Clinical evaluation should focus on the temporal relationship between exposure and the onset of sensory or motor symptoms as well as symptoms of systemic toxicity.

CRITICAL ILLNESS POLYNEUROPATHY Critical illness polyneuropathy (CIP) is a common cause of failure to wean from a ventilator in a patient with associated sepsis and multi-organ failure. Clinical features include generalized or distal flaccid paralysis, especially involving the lower extremities, depressed or absent reflexes, and distal sensory loss with relative sparing of cranial nerve function. The diagnosis can be confirmed with nerve conduction studies showing evidence of a severe, generalized axonal neuropathy. CSF protein should be normal and, in addition to conduction studies, distinguishes CIP from GBS.

Specific Hereditary Polyneuropathies CHARCOT-MARIE-TOOTH DISEASE The eponym Charcot-Marie-Tooth (CMT) identifies a group of heritable disorders of peripheral nerves that share clinical features but differ in their pathologic mechanisms and the specific genetic abnormalities (Web Table 130-4). CMT is the most common heritable neuromuscular disorder, with an incidence of 17 to 40 cases per 100,000. CMT disease usually manifests during the first to second decades with symptoms related to insidious foot drop: frequent tripping and inability to jump well or run as fast as other children. Over time, distal upper extremity weakness develops, resulting in difficulty with buttoning, handling keys, and opening jars. Examination reveals distal weakness and wasting of the intrinsic muscles of the feet, the peroneal muscles, the anterior tibial muscles, and the calves (inverted champagne bottle legs). A variable degree of impaired largefiber sensory function is reflected in reduced vibratory sensation at the toes. Muscle stretch reflexes are lost, first at the ankles. Typically, a foot deformity exists, with high arches (pes cavus) and hammer toes, reflecting long-standing muscle imbalance in the feet. Most patients with CMT disease have nearly normal occupational and daily activities, and they have a normal life span. Although no specific treatment has been developed, the foot drop can be treated by

Chapter 130—Neuromuscular Diseases appropriate bracing of the ankle with ankle-foot orthoses. Genetic counseling and education of affected patients and their families are important, both for reassurance and to preclude unnecessary diagnostic evaluation of affected members in future generations. Demyelinating forms of CMT are classified as CMT1 and axonal forms as CMT2. CMT is usually transmitted as an autosomal dominant trait; however, X-linked dominant transmission is responsible for approximately 10% of cases. Rare autosomal recessive forms are designated CMT4, and these patients tend to have an earlier onset and more severe phenotype. CMT1A is the most common form and accounts for 90% of CMT1 and 50% of all CMT cases. CMT1A is associated with the 17p11.2-p12 duplication in the PMP22 gene expressed by Schwann cells. A deletion or a point mutation of the PMP22 gene produces a different phenotype—HNPP, which is characterized by recurrent episodes of focal entrapment with attacks of weakness and numbness in the peroneal, ulnar, radial, and median nerves (in descending order of frequency) or in a brachial plexus distribution. Commercial testing for the PMP22 duplication or deletion is now widely available.

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Familial Amyloid Neuropathies Amyloid neuropathy is an autosomal dominant disorder caused by extracellular deposition of the fibrillary protein amyloid in peripheral nerve and sensory and autonomic ganglia, as well as around blood vessels in nerves and other tissues. The age of onset varies from 18 to 83 years. In all forms of amyloidosis, the initial and major abnormalities affect the small sensory and autonomic fibers. Involvement of small fibers responsible for pain and temperature sensibilities leads to loss of the ability to perceive mechanical and thermal injuries and to an increased risk of tissue damage. As a result, painless injuries present a major hazard of this disorder; in advanced stages, they can lead to chronic infections or osteomyelitis of the feet or hands and the necessity for amputation. Amyloid deposition in the heart can lead to cardiomyopathy. Mutations in transthyretin, apolipoprotein A1, or gelsolin are responsible. Early recognition is essential, as liver transplantation has been shown to halt disease progression.

Prospectus for the Future The discovery of the cause of some cases of familial amyotrophic lateral sclerosis (ALS) has not yet translated into treatment strategies, nor has it shed light on potential treatments for the more common, clinically identical sporadic syndrome. Genetic and environmental factors that might alter a patient’s predisposition of developing sporadic ALS are also being sought, and with this knowledge comes the hope that novel

References Dyck PJ, Thomas PK (eds): Peripheral Neuropathy, 4th ed. Philadelphia, WB Saunders, 2005. Feldman EL: Amyotrophic lateral sclerosis and other motor neuron diseases. In Goldman L, Ausiello DA (eds): Cecil Textbook of Medicine, 23rd ed. Philadelphia, WB Saunders, 2007.

treatments will soon be developed. In the meantime, many innovative clinical trials are being conducted. The identification of the molecular cause of many of the hereditary peripheral neuropathies has opened the prospect of genetic approaches to treatment. For the acquired neuropathies, symptomatic treatments continue to be developed and improved.

Griggs RC: Neuromuscular diseases: Disorders of the motor neuron and plexus and peripheral nerve disease. In Goldman L, Ausiello DA (eds): Cecil Textbook of Medicine, 23rd ed. Philadelphia, WB Saunders, 2007. Shy M: Peripheral neuropathies. In Goldman L, Ausiello DA (eds): Cecil Textbook of Medicine, 23rd ed. Philadelphia, WB Saunders, 2007.

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Chapter

131

Muscle Diseases Robert C. Griggs

S

keletal muscle diseases (myopathies) are disorders in which a primary structural or functional impairment of muscle occurs. Myopathies can be broadly classified into hereditary and acquired disorders. The hereditary disorders include the muscular dystrophies, congenital myopathies, channelopathies, metabolic disorders, and mitochondrial disorders. The acquired include inflammatory disorders, metabolic disorders, endocrine disorders, disorders associated with systemic illness, and drug-induced or toxic disorders.

Organization and Structure of Muscle Muscle consists of many motor units. The number of muscle fibers innervated by a single motor unit varies from muscle to muscle. Muscles subserving finely coordinated movements, such as an ocular muscle, can have fewer than 10 muscle fibers in a motor unit. Powerful proximal limb muscles have large motor units with 1000 to 2000 fibers innervated by a single motor neuron. The muscle fibers consist of thick and thin filaments (myofibrils). The myofibrils are surrounded by the sarcolemmal membrane and basal lamina. A large number of muscular dystrophies are now known to be caused by genetic defects in this region (Fig. 131-1). The sarcolemmal components are known as the dystrophin-glycoprotein complex (DGC). The DGC is a trans-sarcolemmal complex of proteins and glycoproteins that links the subsarcolemmal cytoskeleton to the extracellular matrix. Dystrophin was the first well-characterized protein in the DGC. Other DGC components include the dystroglycan complex (α and β), the sarcoglycan complex (α, β, γ, and δ), and the syntrophin complex (α, β1, and β2). Closely adherent to the extracellular portion of the sarcolemma is the basal lamina, components of which are known as laminins.

Assessment The most important aspect of evaluating a patient with a myopathy is the history. The most common symptom of a 1182

patient with muscle disease is a loss of function caused by weakness. If the weakness is in the legs, then patients report difficulty climbing stairs and rising from a low chair or toilet or from the floor. When the arms are involved, patients notice trouble lifting objects (especially over their heads) and washing or brushing their hair. These symptoms point to proximal weakness, the most common site of weakness in a myopathy. In less common distal myopathies, patients first complain of poor hand grip (difficulty opening jar tops and turning door knobs) or tripping as a result of ankle weakness from muscle weakness. Rarely they may exhibit a change in speech or swallowing, droopy eyelids, and double vision from weakness of cranial nerve–innervated muscles. The tempo of the disease course is important. Weakness may be present all of the time (fixed) or intermittently (episodic). Myopathies can produce either fixed or episodic symptoms. Muscle disorders can be acute (8 weeks). Examples include (1) acute or subacute inflammatory myopathies (dermatomyositis [DM] and polymyositis [PM]), (2) chronic slow progression over years (most muscular dystrophies), or (3) fixed weakness with little change over decades (congenital myopathies). Patients with channelopathies or metabolic myopathies have recurrent attacks over many years, whereas a patient with acute muscle destruction caused by a toxin such as cocaine may have a single acute episode. Patients who report a generalized global weakness or fatigue seldom have a myopathy, particularly if the neurologic examination findings are normal. Fatigue is a complaint of the patient with myasthenia gravis but otherwise is usually a nonspecific symptom. Muscle pain (myalgia) is also a nonspecific complaint that infrequently accompanies some myopathies. Myalgias may be episodic (e.g., metabolic myopathies) or nearly constant (e.g., occasional inflammatory myopathies). However, muscle pain is surprisingly uncommon in most muscle diseases, and limb pain is more likely to be caused by bone or joint disorders. Rarely is a muscle disease responsible for vague aches and discomfort in muscle if strength is normal. The involuntary muscle cramp is localized to a single muscle and lasts from seconds to minutes. In most instances, cramps are benign and normal; they do not reflect myopathy. Cramps occur with dehydration, hyponatremia, azotemia, and myxedema and

Chapter 131—Muscle Diseases

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Extracellular α2

Basal lamina β1

γ1 Laminin

Dystroglycan Integrin Dgα Iα Iβ

Plasma membrane Dgβ α Syntrophin

β2

β1

Sα Sβ Sδ Sγ

Sarcoglycan

C

Caveolin-3

N Intracellular F-actin

Dystrophin Calpain Dysferlin

Figure 131-1 The dystrophin-glycoprotein complex and related proteins.

in nerve disease such as amyotrophic lateral sclerosis. Muscle contractures are rare and resemble a cramp. They last longer than cramps and occur with exercise in glycolytic enzyme defects. On electromyographic (EMG) examination, contractures are electrically silent, whereas cramps have rapidly firing motor unit discharges. Muscle contracture should not be confused with fixed tendon contracture. Myotonia is the phenomenon of impaired relaxation of muscle after forceful voluntary contraction. Patients report muscle stiffness or persistent contraction in almost any muscle group but particularly the hands. Exercise-induced weakness and myalgias may be accompanied by dark or red urine (myoglobinuria). Myoglobinuria follows rapid muscle destruction.

EXAMINATION Specific muscle function should be tested. Muscle strength is quantitated by the Medical Research Council of Great Britain (MRC) grading scale of 0 to 5: 5: Normal power 4: Active movement against gravity and resistance 3: Active movement against gravity 2: Active movement only with gravity eliminated 1: Trace contraction 0: No contraction Muscles should be inspected for atrophy or hypertrophy. Atrophy of proximal limb muscles is usual in longstanding myopathies. Muscles can also become diffusely hypertrophic

in dystrophic or myotonic conditions. In Duchenne and Becker dystrophies, the calves enlarge as a result of pseudohypertrophy from replacement with connective tissue and fat. The sensory examination findings should be normal in muscle disease. Reflexes are preserved early in the disease process, but when muscles become extremely weak, reflexes become hypoactive or unelicitable. Evidence of upper motor neuron damage (e.g., spasticity, Babinski signs, clonus) is present in myopathies only if coincidental central nervous system disease exists.

PATTERNS OF WEAKNESS Six broad patterns of muscle weakness occur in myopathies: 1. The most common is in proximal muscles of the arms and legs: a limb-girdle distribution. Neck flexor and extensor muscles can also be affected. The reason why most myopathies begin in proximal muscles is unknown. 2. Distal weakness may begin in the upper or lower extrem ities. Such distal weakness is often a feature of neuropathies. 3. Scapuloperoneal weakness includes weakness of the periscapular muscles and distal lower extremity weakness of the anterior compartment. The scapular muscle weakness is usually accompanied by scapular winging. 4. Distal upper extremity weakness in the distal forearm muscles (wrist and finger flexors), and proximal lower extremity weakness involving the knee extensors

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(quadriceps) may occur. This pattern is typical of inclusion body myositis (IBM) and frequent in myotonic dystrophy. 5. Involvement of ocular or pharyngeal muscles may be predominant. 6. Neck extensor weakness (the dropped head syndrome) may be prominent. These six patterns of myopathy are useful in differential diagnosis, but neuromuscular diseases other than myopathies can also exhibit one of these weakness patterns. For example, whereas proximal greater than distal weakness is characteristic of myopathies, patients with acquired demyelinating neuropathies (Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy) often have proximal as well as distal muscle involvement. Such neuropathies are additionally accompanied by sensory and reflex loss. Ocular, pharyngeal, and proximal limb weakness is characteristic of neuromuscular junction transmission disorders such as myasthenia gravis. However, affected patients often have diplopia and weakness that fluctuates, suggesting the correct diagnosis.

MUSCLE BIOPSY Fixed muscle is of little value for diagnosis. Examination of muscle tissue under light microscopy is primarily performed using frozen specimens. The muscle biopsy can establish if either a neuropathic or a myopathic disorder is present; it can also suggest a specific diagnosis of many hereditary and acquired myopathies.

Muscular Dystrophies Muscular dystrophies are inherited myopathies characterized by progressive muscle weakness and degeneration and subsequent replacement by fibrous and fatty connective tissue. Historically, muscular dystrophies were categorized by their distribution of weakness, age at onset, and inheritance pattern. Advances in the molecular understanding of the muscular dystrophies have defined the genetic mutation and abnormal gene product for most of these disorders (Table 131-1). Dystrophinopathies are X-linked disorders resulting from mutations of the large dystrophin gene located at Xp21. Dystrophin is a large subsarcolemmal cytoskeletal protein that, along with the other components of the DGC, provides support to the muscle membrane during contraction. Mutations disrupting the translational reading frame of the gene result in near-total loss of dystrophin (Duchenne dystrophy), whereas in-frame mutations result in the translation of semifunctional dystrophin of abnormal size or amount (Becker dystrophy). The incidence of Duchenne dystrophy is 1 in 3500 male births; one third of the cases result from a new mutation. Duchenne dystrophy manifests as early as age 2 to 3 years as delays in motor milestones and difficulty running. The proximal muscles are the most severely affected, and the course is relentlessly progressive. Patients begin to fall frequently by age 5 to 6, have difficulty climbing stairs by age 8 years, and are usually confined to a wheelchair by age 12. Most patients die of respiratory complications in

their 20s. Congestive heart failure and arrhythmias can occur late in the disease. The smooth muscle of the gastrointestinal tract is involved and may cause intestinal pseudoobstruction. The average IQ of boys with Duchenne dystrophy is low, reflecting central nervous system involvement. Becker dystrophy is a milder form of dystrophinopathy and varies in severity depending on the gene lesion. It is less common than the Duchenne form, with an incidence of 5 per 100,000. Myotonic dystrophy occurs in two forms: DM-1 and DM-2. Both dystrophies are autosomal-dominant multisystem disorders that affect skeletal, cardiac, and smooth muscle and other organs, including the eyes, the endocrine system, and the brain. DM-1 is the most prevalent muscular dystrophy, with an incidence of 13.5 per 100,000 live births. DM-1 can occur at any age, with the usual onset of symptoms in the late second or third decade. However, some affected individuals may remain symptom-free their entire lives. A severe form of DM-1 with onset in infancy is known as congenital myotonic dystrophy. The severity of DM-1 generally worsens from one generation to the next (anticipation). Typical patients exhibit facial weakness with temporalis muscle wasting, frontal balding, ptosis, and neck flexor weakness. Extremity weakness usually begins distally and progresses slowly to affect the proximal limb-girdle muscles. Percussion myotonia can be elicited on examination in most patients, especially in thenar and wrist extensor muscles. Associated manifestations in DM-1 include cataracts, testicular atrophy and impotence, intellectual impairment, and hypersomnia associated with both central and obstructive sleep apnea. Respiratory muscle weakness may be severe, with impairment of ventilatory drive. Cardiac conduction defects are common and can produce sudden death. Pacemakers may be necessary, and annual electrocardiographic examinations are recommended. Chronic hypoxia can lead to cor pulmonale. The molecular defect of myotonic dystrophy (DM-1) is an abnormal expansion of CTG repeats in chromosome 19q13.2. The second myotonic dystrophy (DM-2) is caused by an abnormal expansion of a tetranucleotide repeat on chromosome 3q. The precise pathomechanisms of DM-1 and DM-2 are unknown but probably relate to abnormal RNA transcribed by the pathologic repeats. DM-2 resembles DM-1. However, weakness is often proximal; patients may complain of myotonia and myalgias. Patients with DM-2 may have less severe cardiac and other organ involvement than those with DM-1.

Congenital Myopathies Congenital myopathies are defined by their appearance on biopsy (Table 131-2). They are usually present at birth with hypotonia and subsequent delayed motor development. Most congenital myopathies are relatively nonprogressive and may not be diagnosed until the second or third decade. Clinical findings common in the congenital myopathies are reduced muscle bulk, slender body build, a long, narrow face, skeletal abnormalities (high-arched palate, pectus excavatum, kyphoscoliosis, dislocated hips, and pes cavus), and absent or reduced muscle stretch reflexes. The molecular

Chapter 131—Muscle Diseases

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Table 131-1 Major Muscular Dystrophies Disease

Mode of Inheritance

Gene Mutation Location

Gene Defect or Protein

XR XR

Xp21 Xq28

Dystrophin Emerin

AD AD AD AR AR AR AR AR AR AR AR AR AR

5q22-34 1q11-21 3p25 15q15 2p12 13q12 17q12 4q12 5q33 17q11 9q31 19q13.3 2q31

Myotilin Lamin A/C Caveolin-3 Calpain-3 Dysferlin γ-sarcoglycan α-sarcoglycan β-sarcoglycan δ-sarcoglycan Telethonin E3-ubiquitin-ligase Fukutin-related protein 1 Titin

AR AR AR

9q31-33 9q31-33 1p

Fukutin Fukutin Glycosyltransferase

Merosin-deficient classic type Merosin-positive classic type Integrin-deficient CMD

AR AR AR

6q2 Unknown 12q13

Laminin-2 (merosin) Not known Integrin α7

Rigid spine syndrome

AR

1p3

Selenoprotein N

AD AD AR AR AD

2p15 2q31 9p1-q1 2q12-14 14

Unknown Titin GNE Dysferlin MYH7

AD AD AD AD AD AD AD

4q35 14q11 19q13 3q 11q21-23 2q35 21q22

Deleted chromatin Poly(A) binding protein 2 RNA accumulation RNA accumulation β-crystallin Desmin Collagen VI

X-Linked MD Duchenne, Becker Emery-Dreifuss Limb-Girdle MD LGMD LGMD LGMD LGMD LGMD LGMD LGMD LGMD LGMD LGMD LGMD LGMD LGMD

1A 1B 1C 2A 2B* 2C 2D 2E 2F 2G 2H 2I 2J

Congenital MD With CNS Involvement Fukuyama CMD Walker-Warburg CMD Muscle-eye-brain CMD Without CNS Involvement

Distal MD Late adult-onset 1A (Welander) Late adult-onset 1B (Udd) Early adult-onset 1A (Nonaka) Early adult-onset 1B (Miyoshi)† Early adult-onset 1C (Laing) Other MD Facioscapulohumeral Oculopharyngeal Myotonic dystrophy type 1 Myotonic dystrophy type 2 Myofibrillar myopathy Myofibrillar myopathy Bethlem myopathy

*Probably the same condition as Miyoshi distal MD. † Probably the same condition as LGMD 2B. AD, autosomal dominant; AR, autosomal recessive; CMD, congenital muscular dystrophy; CNS, central nervous system; GNE, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase; LGMD, limb-girdle muscular dystrophy; MD, muscular dystrophy; XR, X-linked recessive; MYH7, myosin heavy chain 7.

Table 131-2 Major Morphologically Distinct Congenital Myopathies Central core Nemaline Centronuclear (myotubular) Congenital fiber type disproportion Sarcotubular Reducing body Myofibrillar

genetic defects of most congenital myopathies are now known, and these disorders, as well as the muscular dystrophies, are being reclassified.

Metabolic Myopathies Metabolic myopathies (Table 131-3) include (1) glucose and glycogen metabolism disorders, (2) lipid metabolism disorders, and (3) mitochondrial disorders.

GLUCOSE AND GLYCOGEN METABOLISM DISORDERS Glucose, and its storage form glycogen, is essential for the short-term, predominantly anaerobic energy requirements

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of muscle. Disorders of glucose and glycogen metabolism (called glycogenoses) have two distinct syndromes: (1) dynamic symptoms of exercise intolerance, pain, cramps, and myoglobinuria; and (2) static symptoms of fixed weakness without exercise intolerance or myoglobinuria. Of the Table 131-3 Metabolic and Mitochondrial Myopathies Glycogen Metabolism Deficiencies Type II α1,4-glucosidase (acid maltase) Debranching enzyme Type III Type IV Branching enzyme Type V Phosphorylase* (McArdle disease) Type VII Phosphofructokinase* (Tarui disease) Phosphorylase β kinase* Type VIII Phosphoglycerate kinase* Type IX Type X Phosphoglycerate mutase* Lactate dehydrogenase* Type XI Lipid Metabolism Deficiencies Carnitine palmitoyl transferase* Primary systemic or muscle carnitine deficiency Secondary carnitine deficiency Mitochondrial Myopathies Pyruvate dehydrogenase complex deficiencies Progressive external ophthalmoplegia (PEO) Autosomal dominant with multiple mitochondrial DNA deletions Adenine nucleotide translocator 1 (ANT1) Twinkle (mitochondrial protein) Polymerase gamma Kearns-Sayre syndrome Myoclonic epilepsy and ragged-red fibers (MERRF) Mitochondrial encephalopathy with lactic acidosis and strokelike episodes (MELAS) Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) Mitochondrial depletion syndrome Leigh disease and neuropathy, ataxia, retinitis pigmentosa (NARP) Succinate dehydrogenase deficiency* *Deficiency can produce exercise intolerance and myoglobinuria.

11 glycogenoses, only glucose 6-phosphate (type I) and liver phosphorylase (type VI) deficiencies spare muscle.

Glycogenoses with Exercise Intolerance (Myoglobinuria) Exercise intolerance (Table 131-4) begins in childhood with exertional muscle pain, cramps, and myoglobinuria appearing in the second or third decade. Many patients note a second wind phenomenon after a period of brief rest so that they can continue the exercise at the previous level of activity. Muscle pain is caused by electrically silent contractures. Strength, blood creatine kinase (CK) levels, and EMG findings between attacks are usually normal early in the disease, but they may become abnormal with advancing age. After episodes of severe myoglobinuria, EMG shows myopathic units and fibrillations. EMG performed during a contracture shows electrical silence. In the forearm exercise test, the venous lactate level fails to rise in myophosphorylase, phosphofructokinase, and phosphoglycerate kinase deficiencies and rises subnormally in phosphorylase β kinase, phosphoglucomutase, and lactate dehydrogenase deficiencies. Diagnosis is made by muscle biopsy study of the enzymes or by defining specific genetic mutations.

Glycogenoses with Fixed Weakness and No Exercise Intolerance Glycogenoses with fixed weakness and no exercise intolerance (see Table 131-3) produce a syndrome of progressive proximal weakness. Diagnosis requires muscle biopsy or genetic mutation definition. Acid maltase deficiency can now be treated with enzyme replacement.

DISORDERS OF FATTY ACID METABOLISM Lipids are essential for the aerobic energy needs of muscle during sustained exercise. Serum long-chain fatty acids are the primary lipid fuel for muscle metabolism. They are transported into the mitochondria as carnitine esters and

Table 131-4 Channelopathies and Related Disorders Disorder

Clinical Features

Inheritance

Chromosome

Gene

Myotonia Myotonia and weakness

Autosomal dominant Autosomal recessive

7q35 7q35

CLC-1 CLC-1

Paramyotonia Periodic paralysis, myotonia, and paramyotonia Periodic paralysis

Autosomal dominant Autosomal dominant

17q13.1-13.3 17q13.1-13.3

SCNA4A SCNA4A

Autosomal dominant

17q13.1-13.3

SCNA4A

Periodic paralysis (most cases) Anesthetic-induced delayed relaxation Periodic paralysis, cardiac arrhythmia, skeletal abnormalities Muscle mounding or stiffness

Autosomal dominant

1q31-32

Autosomal dominant

19q13.1

Autosomal dominant

17q23

Dihydropyridine receptor Ryanodine receptor KCNJ2

Autosomal dominant

1q41

Caveolin-3

Chloride Channelopathies Myotonia congenita Thomsen disease Becker disease Sodium Channelopathies Paramyotonia congenita Hyperkalemic periodic paralysis Hypokalemic periodic paralysis (men

Childhood and adult

Proximal >distal

Increased (up to 50× normal)

Polymyositis

Women >men

Adult

Proximal >distal

Inclusion body myositis

Men >women

Elderly (>50 yr)

Proximal and distal; predilection for finger and wrist flexors, knee extensors

Increased (up to 50× normal) Increased (7.5) with forced diuresis are effective in lowering the blood concentration. For patients with hemodynamic compromise refractory to aggressive supportive therapy, barbiturate elimination can be increased by hemodialysis or charcoal hemoperfusion. The effective treatment of withdrawal symptoms requires estimating the daily dose of the abused drug and substituting an equivalent phenobarbital dose to stabilize the patient, after which the dose of phenobarbital is tapered over 4 to 14 days, depending on the half-life of the abused drug. Benzodiazepines may also be used for detoxification, and propranolol and clonidine may help reduce symptoms. Abuse of γ-hydroxybutyrate (GHB) has increased substantially over the last decade in the United States. This drug is abused for its sedative, euphoric, and bodybuilding effects. GHB is a metabolite of the neurotransmitter GABA, and it also influences the dopaminergic system. It potentiates the effects of endogenous or exogenous opiates. The ingestion of GHB results in immediate drowsiness and dizziness, with the feeling of a high. These effects can be potentiated by the

Chapter 135—Alcohol and Substance Abuse concomitant use of alcohol or benzodiazepines. Similar to flunitrazepam and ketamine, GHB is a popular club drug, and it has been implicated in cases of date rape. Its street names include G, liquid E, liquid X, fantasy, Georgia home boy, and grievous bodily harm. Adverse effects that may occur within 15 to 60 minutes of its ingestion include headache, nausea, vomiting, hallucinations, loss of peripheral vision, nystagmus, hypoventilation, cardiac dysrhythmias, seizures, and coma. In rare instances these adverse effects have led to death. The withdrawal from GHB becomes clinically apparent within 12 hours and may last up to 12 days.

OPIOIDS Opioids include the natural and semisynthetic alkaloid derivatives of opium, as well as the purely synthetic drugs that mimic heroin. They bind to opioid receptors in the brain, spinal cord, and gastrointestinal tract; in addition, they act on several other CNS neurotransmitter systems, including dopamine, GABA, and glutamate, to produce analgesia, CNS depression, and euphoria. With continued opioid use, tolerance and physical dependence develop. As a result, the user must use larger amounts of the drug to obtain the desired effect, and withdrawal symptoms may occur if use is discontinued. The commonly abused opioids include heroin, morphine, codeine, oxycodone (OxyContin or Roxicodone), meperidine (Demerol), propoxyphene (Darvon), hydrocodone (Vicodin), hydromorphone (Dilaudid), buprenorphine (Temgesic) and fentanyl (Sublimaze). Intravenous heroin use, particularly when combined with cocaine (a so-called speedball), is increasing in the United States. The controlled-release pain reliever OxyContin was made available for use in 1995. By 2001, OxyContin was the most prescribed brand-name narcotic and was frequently diverted for illicit use, in which it was ingested orally, inhaled, or dissolved in water and administered intravenously to obtain an immediate high. In 2002, buprenorphine (Subutex) was made available in the United States for use in opiate addiction therapy. Unlike methadone, which must be dispensed from a clinic, buprenorphine can simply be prescribed by a physician. As a result, its illicit use has increased substantially. Acute opioid overdose produces pulmonary congestion, with resultant cyanosis and respiratory distress, and changes in mental status that may progress to coma. Other manifestations include fever, pinpoint pupils, and seizures. Unsterile intravenous practices can lead to skin abscesses, cellulitis, thrombophlebitis, wound botulism, meningitis, rhabdomyolysis, endocarditis, hepatitis, or human immunodeficiency virus (HIV) infection. Neurologic complications from intravenous heroin use include transverse myelitis, inflammatory polyneuropathy, and peripheral nerve lesions. For acute opioid overdose, the patient’s respiratory status must be assessed and supported. Naloxone should be administered intravenously and repeated at 2- to 3-minute intervals, often in escalating doses. The patient should respond within minutes with increases in pupil size, respiratory rate, and level of alertness. If no response occurs, opioid overdose is excluded, and other causes of somnolence and respiratory depression must be considered. Naloxone should be titrated carefully because it may precipitate acute withdrawal symptoms in opioid-dependent patients.

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Withdrawal symptoms may appear as early as 6 to 10 hours after the last injection of heroin. Initially the individual often has feelings of drug craving, anxiety, restlessness, irritability, rhinorrhea, lacrimation, diaphoresis, and yawning; these signs are followed by dilated pupils, piloerection, anorexia, nausea, vomiting, diarrhea, abdominal cramps, bone pain, myalgias, tremors, muscle spasms, and, in rare cases, seizures. These symptoms and signs peak at 36 to 48 hours and then subside over 5 to 10 days, if untreated. A protracted abstinence syndrome characterized by bradycardia, hypotension, mild anxiety, sleep disturbance, and decreased responsiveness may occur for up to 5 months. Withdrawal from opioids can be managed with methadone, a long-acting synthetic agonist drug; withdrawal symptoms of methadone develop more slowly and are less severe than those caused by heroin. Methadone can be given twice daily and tapered over 7 to 10 days. Alternatively, levo-α-acetylmethadol (LAAM), a long-acting agonist, or buprenorphine, a partial agonist, can be given. The latter is combined with naloxone in a formulation (Suboxone) developed to decrease the potential for abuse. Clonidine reduces autonomic hyperactivity and is particularly effective if combined with a benzodiazepine. Patients with repeated relapses can be maintained on methadone or LAAM. Buprenorphine may also be used as maintenance therapy. Naltrexone is a long-acting opioid antagonist that blocks impulsive opioid use. It can be given daily or two to three times weekly, but only after the patient is thoroughly detoxified because it may precipitate withdrawal. Pharmacotherapy must be combined with psychotherapy and structured rehabilitation to achieve an optimal outcome.

AMPHETAMINES Amphetamines have been used therapeutically for weight reduction and treatment of attention-deficit disorder and narcolepsy. Similar to cocaine, they cause a release of monoamine neurotransmitters (dopamine, norepinephrine, and serotonin) from presynaptic neurons. In addition, however, they have neurotoxic effects on dopaminergic and serotonergic neurons. Their euphoric and reinforcing effects are mediated through dopamine and the mesolimbic system, whereas their cardiovascular effects are caused by the release of norepinephrine. Chronic use leads to neuronal degeneration in dopamine-rich areas of the brain, which may increase the risk for the eventual development of Parkinson disease. Amphetamines can be abused orally, intranasally, intravenously, or by smoking. The most frequently used drugs are dextroamphetamine (Dexedrine), methamphetamine (Desoxyn), and methylphenidate (Ritalin). Methamphetamine is known on the street as ice, crank, meth, crystal, tina, glass, and yaa baa. Recently the illicit use of amphetamines has increased substantially, in part because (1) it is easily and quickly synthesized from ephedrine or pseudoephedrine (Fig. 135-4), and (2) its psychotropic effects persist for up to 24 hours. The anorexiants phenmetrazine and phentermine, which are structurally and pharmacologically similar to amphetamine, also have been used illicitly. Tolerance to the stimulant effects of amphetamines develops rapidly, and toxic effects can occur with higher doses. Acute amphetamine toxicity is characterized by excessive

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Section XXII—Substance Abuse Ephedrine OH

Pseudoephedrine OH H N

Amphetamine NH2

H N

Methamphetamine H N

Figure 135-4 The chemical structures of amphetamine and methamphetamine, which can be easily manufactured from ephedrine or pseudoephedrine given that they are structurally similar and widely available.

sympathomimetic effects, including tachycardia, hypertension, hyperthermia, cardiac arrhythmias, tremors, seizures, and coma. The patient may experience irritability, hyper vigilance, paranoia, stereotyped compulsive behavior, and tactile, visual, or auditory hallucinations. The clinical picture may simulate an acute schizophrenic psychosis. The symptoms of withdrawal are similar to those seen with cocaine (described in the next section), but the acute psychosis and paranoia are often significantly pronounced. The treatment of amphetamine abuse centers on a quiet environment, benzodiazepines for anxiety, and sodium nitroprusside for severe hypertension. Antipsychotics, such as haloperidol, can reduce the agitation and psychosis by blocking dopamine’s effects on the CNS receptor. Urine acidification with ammonium chloride accelerates amphetamine excretion.

Illicit Drug Abuse COCAINE Cocaine use has increased dramatically among adolescents and young adults. Among individuals 12 years old or older in 2007, 2.1 million had used cocaine within the previous month and 906,000 had used it for the first time within the previous 12 months, which averages to about 2500 initiates per day. It is a frequent cause of drug-related visits to emergency rooms. Cocaine can be taken orally or intravenously; alternatively, because it is well absorbed through all mucous membranes, abusers may achieve a high blood concentration after intranasal, sublingual, vaginal, or rectal administration. Its freebase form—called crack because of the popping sound it makes when heated—is heat stable so that it can be smoked. Crack cocaine is considered to be the most potent and addictive form of the drug. Euphoria occurs within seconds after crack cocaine is smoked and is short lived. Compared with smoking of crack cocaine or the intravenous injection of the drug, mucosal administration results in a slower onset of action, a later peak effect, and a longer duration of action. The blood half-life is approximately

1 hour. The drug’s major metabolite is benzoylecgonine, which can be detected in the urine for 2 to 3 days after a single dose. An intense, pleasurable reaction lasting 20 to 30 minutes occurs after cocaine use, after which rebound depression, agitation, insomnia, and anorexia occur, which are then followed by fatigue, hypersomnolence, and hyperphagia (the crash). This crash usually lasts 9 to 12 hours but occasionally may last up to 4 days. Users often ingest the drug repetitively at relatively short intervals to recapture the euphoric state and to avoid the crash. On occasion, sedatives or alcohol are ingested concomitantly to reduce the intensity of anxiety and irritability associated with the crash. The combination of cocaine and intravenously administered heroin (so-called speedball, snowball, Belushi, or dynamite) is frequently used so that the abuser can experience the cocaine-induced euphoria and then float down on the opiate. Unfortunately, this combination has been reported to cause sudden death. People who use cocaine in temporal proximity to the ingestion of ethanol produce the metabolite cocaethylene, which has also been implicated in cocaine-related deaths. Cocaine blocks the presynaptic reuptake of norepinephrine and dopamine, producing an excess of these neuro transmitters at the site of the postsynaptic receptor. Thus cocaine acts as a powerful sympathomimetic agent, resulting in tachycardia, hypertension, tachypnea, hyperthermia, agitation, pupillary dilation, peripheral vasoconstriction, and seizures. Cocaine causes potent vasoconstriction of cerebral arteries and therefore may result in a stroke. It is associated with myocardial ischemia and arrhythmias and, in rare cases, with myocardial infarction in young persons with normal or nearly normal coronary arteries. The principal mechanisms of ischemia and infarction are coronary arterial vasoconstriction, thrombosis, platelet aggregation, tissue plasminogen activator inhibition, increased myocardial oxygen demand, and accelerated atherosclerosis (Fig. 135-5). For patients with cocaine-induced hypertension or tachycardia, labetalol and benzodiazepines are usually effective in lowering systemic arterial pressure and heart rate. Patients with acute myocardial infarction should receive aspirin, heparin, nitroglycerin, and, if indicated, reperfusion therapy (with a thrombolytic agent or primary coronary intervention). The use of β-adrenergic blockers should be avoided because ischemia may be worsened by unopposed α-adrenergically mediated coronary arterial vasoconstriction. Patients with a normal electrocardiogram or nonspecific changes can be managed safely with observation. The immediate treatment of acute cocaine intoxication includes obtaining vascular and airway access, if needed, and careful electrocardiographic monitoring. Benzodiazepines can be given to control CNS agitation, and haloperidol or risperidone can be used in the severely agitated patient. A supportive environment is needed, but detoxification is not required, given that few physical signs of true dependence are present. Most chronic cocaine abusers have psychological dependence and an intense craving for cocaine. Personal and group therapies are important adjuncts to pharmacologic treatment, but relapse is common and is difficult to manage. Although no medication is FDA approved for treatment of cocaine addiction, disulfiram, modafinil, anticonvulsants

Chapter 135—Alcohol and Substance Abuse

Increased heart rate Increased blood pressure Increased myocardial contractility

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Increased myocardial oxygen demand with limited oxygen supply

Atherosclerotic plaque

Increased α-adrenergic stimulation Increased endothelin production Increased nitric oxide production

Vasoconstriction Smooth muscle cell

Platelets Fibrin Increased plasminogen-activator inhibitor Increased platelet activation and aggregability Increased endothelial permeability

Accelerated atherosclerosis and thrombosis Atherosclerotic plaque

Figure 135-5 The mechanisms by which cocaine may induce myocardial ischemia or infarction. Cocaine may cause increases in the determinants of myocardial oxygen demand when oxygen supply is limited (top), when intense vasoconstriction of the coronary arteries occurs (middle), or when accelerated atherosclerosis and thrombosis are present (bottom).

(e.g., topiramate and tiagabine), serotonin reuptake inhibitors (e.g., citalopram), serotonin receptor antagonists (e.g., ondansetron), and GABA receptor agonists (e.g., baclofen) have shown some promise in promoting cocaine abstinence. More recent research is focused on so-called vaccine strategies, whereby protein-conjugated analogues of cocaine would be administered to produce anti-cocaine antibodies that bind cocaine, thereby preventing its passage across the blood-brain barrier.

CANNABIS The cannabinoid drugs include marijuana (the dried flowering tops and stems of the hemp plant) and hashish (a resinous extract of the hemp plant). Marijuana is the illicit drug with the highest rate of dependence or abuse. Of the 6.9 million persons in the United States with dependence on or abuse of illicit drugs in 2007, 3.9 million were dependent on or abused marijuana or hashish (representing 1.6% of the total population aged 12 years old or older). Marijuana and hashish are among the drugs most commonly used by adolescents, with approximately one half of 12th graders admitting use at least once and 20% reporting that they are current users. Most of their pharmacologic effects come from metabolites of δ-9-tetrahydrocannabinol, which bind to specific cannabinoid receptors located in the CNS, spinal cord, and peripheral nervous system. The primary mode of use is smoking, with mood-altering

and intoxicating effects noted within 3 minutes and peak effects in approximately 1 hour. The acute physiologic effects are dose related and often include increased heart rate, conjunctival congestion, dry mouth, fine tremor, muscle weakness, and ataxia. Psychoactive effects include euphoria, enhanced perception of colors and sounds, drowsiness, inattentiveness, and inability to learn new facts. Tolerance and physical dependence occur, and chronic users may experience mild withdrawal symptoms of irritability, restlessness, anorexia, insomnia, or mild hyperthermia. Rarely, acute psychosis with panic reactions occurs. The treatment of withdrawal is supportive and includes reassurance; benzodiazepines may be used in severely agitated patients. Cannabinoids have been used as antiemetic agents in patients with cancer receiving chemotherapy, for weight stimulation (in patients with cancer or HIV infection), and in the treatment of glaucoma.

HALLUCINOGENS AND DISSOCIATIVE DRUGS Hallucinogens (drugs that cause hallucinations) include lysergic acid diethylamide (LSD), mescaline, psilocybin, and ibogaine. Dissociative drugs distort perceptions of sight and sound and produce feelings of detachment—dissociation— without causing hallucinations. They include phencyclidine (PCP), ketamine, and dextromethorphan (a widely available cough suppressant).

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Section XXII—Substance Abuse

LSD is the most potent of the hallucinogenic drugs. Although it is known to interact with serotonin receptors in the cerebral cortex and locus ceruleus, the precise psycho active mechanism is unknown. Within 30 minutes of its oral ingestion, sympathomimetic effects appear, including mydriasis, hyperthermia, tachycardia, elevated blood pressure, diaphoresis, dry mouth, increased alertness, tremors, and nausea. Within 2 hours, the psychoactive effects become apparent, with heightened perceptions (highly intensified colors, smells, sounds, and other sensations), body distortions, mood variations, and visual hallucinations. An acute panic reaction may occur, sometimes leading to self-injury or suicide. After approximately 12 hours, the syndrome begins to subside, but fatigue and tension may persist for another day. Flashbacks (brief recurrences of the hallucinations) may occur days or even weeks after the last dose but tend to disappear without treatment. Acute panic reactions are best treated in a supportive environment; benzodiazepines can be given to severely agitated patients. PCP is a potent addictive hallucinogen that produces a prompt stimulant effect similar to that of amphetamines, with feelings of euphoria, power, and invincibility. Patients may have hypertension, tachycardia, hyperthermia, bidirectional nystagmus, slurred speech, ataxia, hallucinations, extreme agitation, and rhabdomyolysis. With more severe reactions, patients may be brought to medical attention in a coma-like state, with open eyes and pupils that are partially dilated, a decreased pain response, brief periods of excitation, and muscle rigidity. On occasion, patients may have hypertensive urgency, seizures, and bizarre (often violent) behavior, which lead to suicide or extreme violence toward others. Tolerance and mild withdrawal symptoms have been seen in daily users, but the major problem is drug craving. Treatment entails a quiet environment, sedation with benzodiazepines, hydration, haloperidol for terrifying hallucinations, and suicide precautions. Continuous gastric suction and acidification of the urine with intravenous ammonium chloride or ascorbic acid may aid in the drug’s excretion, but acidification may increase the risk of renal failure if rhabdomyolysis is present. Ketamine is a rapidly acting general anesthetic; unlike most anesthetics, it produces only mild respiratory depression and appears to stimulate the cardiovascular system. Adverse effects, including delirium and hallucinations, limit the use of ketamine as a general anesthetic in humans. Similar to PCP, ketamine is a dissociative anesthetic. In addition, it has both analgesic and amnestic properties and is associated with less confusion, irrationality, and violent behavior than PCP. Ketamine is one of the club drugs that has been implicated in date rape.

INHALANTS The inhalants may be classified as (1) organic solvents, including toluene (airplane glue and spray paint), paint thinners, kerosene, gasoline, carbon tetrachloride, shoe polish, acetone (nail polish removers and Liquid Paper), xylene (permanent markers), and degreasers (dry cleaning fluids); (2) gases, such as butane, propane, aerosol propellants, and anesthetics (ether, chloroform, halothane, and nitrous oxide); and (3) nitrites, such as cyclohexyl nitrite, amyl nitrite, and

butyl nitrite (room deodorizer). These drugs are most often inhaled by children or young adolescents, after which they produce dizziness and intoxication within minutes. Prolonged exposure or daily use may lead to hearing loss, bone marrow depression, cardiac arrhythmias, cerebral degeneration, peripheral neuropathies, and damage to the liver, kidneys, or lungs. A characteristic “glue sniffer’s rash” around the nose and mouth is sometimes seen after prolonged use. In rare instances death may occur, most likely from hypoxemia, cardiac arrhythmias, pneumonia, or aspiration of vomit while unconscious. Detoxification is rarely required for the patient who has abused these substances, but psychiatric treatment may be needed to prevent relapse.

DESIGNER DRUGS The term designer drugs refers to illicit synthetic drugs, many of which have increased potency in comparison with their parent compounds. The most common designer drugs include analogs of fentanyl, meperidine, piperazine, and methamphetamines. The best-known fentanyl derivatives are α-methyl fentanyl (China white), parafluorofentanyl, and 3-methyl fentanyl. Because these drugs are approximately 1000 times as potent as heroin, the fact that fatal overdoses from respiratory depression have been reported is not surprising. The major meperidine derivatives are 1-methyl-4-phenyl4-propionoxypiperidene (MPPP) and 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP). These drugs produce euphoria similar to that caused by heroin. In some users, MPTP causes neuronal degeneration in the substantia nigra, which produces an irreversible form of Parkinson disease. Piperazines, a new class of designer drugs of abuse, are commonly sold as party pills in the form of tablets, capsules, or powders on the drug black market and in so-called “head shops” or over the internet. 1-Benzylpiperazine (BZP) is the most prevalent of these compounds. Aside from BZP and 1-(3,4-methylenedioxybenzyl)piperazine (MDBP), the phenylpiperazine derivatives 1-(3-trifluoromethylphenyl) piperazine (TFMPP), 1-(3-chloro phenyl) piperazine (mCPP), and 1-(4-methoxyphenyl)piperazine (MeOPP) are often abused. Because piperazines and amphetamines cause similar pharmacologic symptoms, piperazine poisoning can easily be wrongly diagnosed as amphetamine poisoning. Furthermore, piperazines are not detected by routinely used immunochemical screening procedures for drugs of abuse, but they require an appropriate toxicologic analysis (e.g., by gas chromatography–mass spectrometry). The methylenedioxy synthetic derivatives of amphetamine and methamphetamine are generally referred to as ecstasy and include 3,4-methylenedioxy methamphetamine (MDMA, also known as Adam); 3,4-methylenedioxyethylamphetamine (MDEA, also known as Eve); and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB, also known as Methyl-J or Eden). These drugs have CNS stimulant and hallucinogenic properties. They produce elevated mood and increased self-esteem and may cause acute panic, anxiety, paranoia, hallucinations, tachycardia, nystagmus, ataxia, and tremor. Deaths in some users have been attributed to cardiac arrhythmias, hyperthermia with seizures, and intracranial hemorrhage.

Chapter 135—Alcohol and Substance Abuse

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Prospectus for the Future The elucidation of ligands to psychotropic drugs is being used to provide molecular clues for the derivation of structural analogs that have therapeutic benefits. For example, recent studies have identified the receptors to which tetrahydrocannabinoid binds to mediate its effects. In the brain, activation of the cannabinoid-1 receptor causes the psychotropic effects associated with marijuana use. Cannabinoid-1 receptors also are found in adipose tissue and the gastrointestinal tract, where they regulate food intake and glycemic control. A cannabinoid-1 receptor antagonist, rimonabant, has been

References Anton RF: Naltrexone for the management of alcohol dependence. N Engl J Med 359:715-721, 2008. Anton RF, O’Malley SS, Ciraulo DA, et al: Combined pharmacotherapies and behavioral interventions for alcohol dependence: The COMBINE study: A randomized controlled trial. JAMA 295:2003-2017, 2006. Dick DM, Agrawal A: The genetics of alcohol and other drug dependence. Alcohol Res Health 31:111-118, 2008. Edenberg HJ: The Genetics of Alcohol Metabolism: Role of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Variants. Available at: http://pubs.niaaa.nih.gov/ publications/arh301/5-13.htm. Ferri MMF, Amato L, Davoli M: Alcoholics Anonymous and other 12-step programmes for alcohol dependence. Cochrane Database Syst Rev 4:1-26, 2008.

shown to be effective in suppressing the reinforcing and rewarding properties of different agents that are often abused (e.g., cocaine, nicotine, alcohol) and reducing food intake and body weight. This agent appears to be effective in treating drug addiction and obesity-related disorders, although its high rate of adverse psychiatric effects (i.e., depression, anxiety, and suicidal ideation) have halted its clinical development. The identification of other receptors and signaling pathways may permit the development of other agonists or antagonists that will serve as effective pharmacotherapeutic agents.

Heilig M, Mark E: Pharmacological treatment of alcohol dependence: Target symptoms and target mechanisms. Pharmacol Ther 111:855-876, 2006. Lopez-Moreno JA, Gonzalez-Cuevas G, Moreno G, Navarro M: The pharmacology of the endocannabinoid system: Functional and structural interactions with other neurotransmitter systems and their repercussions in behavioral addiction. Addict Biol 13:160-182, 2008. Preti A: New developments in the pharmacotherapy of cocaine abuse. Addict Biol 12:133-151, 2007. Saitz R: Unhealthy alcohol use. N Engl J Med 352:596-607, 2005. Staack RF: Piperazine designer drugs of abuse. Lancet 369:1411-1413, 2007. Substance Abuse and Mental Health Services Administration: Results from the 2007 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-34, DHHS Publication No. SMA 08-4343). Rockville, Md, 2008. Available at: http://oas.samhsa.gov.


Index Page numbers followed by f indicate figures; t, tables. A A1c (glycosylated hemoglobin), 698, 703-704, 704t, 706 Abatacept, for rheumatoid arthritis, 827, 827t Abciximab, 109-110, 582 Abdominal pain, 382-385, 383t, 384f in acute intermittent porphyria, 655-656 gastrointestinal bleeding with, 387 in pancreatic carcinoma, 453 in pancreatitis acute, 447-448 chronic, 451-452 Abdominal pain syndrome, functional, 385 Abortion, septic, acute kidney injury secondary to, 367-368 Abscess(es) antimicrobial therapy for, 905 brain, 1159-1160, 1160f infective endocarditis with, 962, 1162-1163 parasitic, 942, 943f subdural empyema leading to, 1160 fever of unknown origin and, 921 hepatic, 921, 975-976, 976t infective endocarditis with, 961-963, 1162-1163 surgery for, 966 intra-abdominal, 975-977, 976t fever associated with, 921, 975 lung, 248, 256 pancreatic, 976t, 977 paravertebral, in mycobacterial osteomyelitis, 988 pelvic, 976t, 977 perinephric, 976t, 990-991 peritonsillar, 949 pharyngeal space, 949-950 prostatic, 757, 922, 991 renal, 922, 962 retroperitoneal, 976t, 977 retropharyngeal space, 949-950 spinal epidural, 987, 1161-1162, 1161f staphylococcal, 886-887 subcutaneous, 969 Absence epilepsy childhood, 1146, 1149-1150 juvenile, 1146 Absence seizures, 1145-1146, 1145f atypical, 1146 frontal, 1144 hyperventilation and, 1147 Absence status epilepticus, 1151 Absolute risk reduction, 18 Abuse. See Domestic violence; Elder abuse. Acamprosate, for alcoholism, 1224 Acanthocytes, 529 Acarbose, 710t-713t, 712 Accessory pathways, 129 catheter ablation of, 142-143 concealed, 129 ACE. See Angiotensin-converting enzyme (ACE). ACE inhibitors. See Angiotensin-converting enzyme (ACE) inhibitors. Acetaminophen for osteoarthritis pain, 872 overdose of, 264t, 472, 477 Acetazolamide, mechanism of action, 307-308, 308t Acetylcholine, neuromuscular junction disease and, 1191-1193 Acetylcholinesterase inhibitors, for dementia symptoms in Alzheimer disease, 1072, 1074 in Parkinson disease, 1075 N-Acetylcysteine for acetaminophen overdose, 472 contrast media–associated nephropathy and, 365-366, 371-372 for idiopathic pulmonary fibrosis, 230 in Wilson disease, 652 Achalasia, 411, 412f, 412t Achilles tendinitis, 875

Acid-base balance, 294-295, 316-319, 317f Acid-base disorders, 316-319. See also Acidosis; Alkalosis. adaptive responses to, 317, 318t systematic assessment of, 317, 317t Acidosis as ketoacidosis, 318-319 diabetic, 698, 715-716, 715t metabolic. See Metabolic acidosis. renal tubular, 319, 319f-320f, 319t urinary pH in, 299-300, 320 respiratory, 321-322 Acquired cystic kidney disease, 339 Acquired immunodeficiency syndrome (AIDS), 884. See also Human immunodeficiency virus (HIV) infection. antiretroviral therapy for, initiation of, 1016t, 1017 chest infections in, 194 cholecystitis in, acalculous, 492 diagnostic criteria for, 1009, 1009t enteric protozoal infections in, 1024-1025 epidemiology of, 1008-1010, 1010f malignancies in, 1009t, 1026. See also Kaposi sarcoma. non-Hodgkin lymphoma, 553, 1025-1026 primary CNS lymphoma, 1026, 1154, 1157 nervous system disease in, 1021-1023, 1022t-1023t, 1177 progression to, 1012f, 1013-1014, 1017f travel by patients with, 1037 travelers’ risk of acquiring, 1037 Acromegaly, 662-663, 662t-663t hyperphosphatemia in, 791-792 musculoskeletal manifestations of, 881t Acropachy, thyroid, 882 ACTH. See Adrenocorticotropic hormone (ACTH). Actin, of myocytes, 25, 25f-26f Actinomyces, 887-888 Actinomycetales, 887-888 Actinomycin D, mechanism of action, 4 Action potentials cardiac, 118, 119f hyperkalemia and, 312 Action tremor, 1114 Activated protein C, 561. See also Protein C. for sepsis syndrome, 930-932, 931t for septic shock, 262 Activated protein C resistance, 582-583, 582t, 587 Activities of daily living (ADLs), 1198-1199, 1205-1207 Acute chest syndrome, in sickle cell disease, 530 Acute coronary syndromes, 106-112. See also Myocardial infarction; Unstable angina. glycoprotein IIb/IIIa inhibitors in, 582 plaque disruption and, 95 secondary prevention of, 116-117 treatment algorithm for, 109f Acute intermittent porphyria, 655-656, 655f, 656t Acute kidney injury (AKI), 359-368. See also Acute tubular necrosis (ATN) ; Renal failure, acute. causes of, 359, 360f aortic dissection as, 349-350 endogenous nephrotoxins, 367-368 exogenous nephrotoxins, 365-366, 365t in chronic kidney disease, 372, 372f, 372t vs. chronic kidney disease, 362, 363t, 369 clinical importance of, 359, 360t definition of, 359 diagnostic criteria for, 359, 359b future prospects for, 368b in hospitalized patients, 360 with chronic kidney disease, 372 diagnostic approach to, 360-361, 361t-362t hyperkalemia in, 364 in outpatients, 362-363, 363t of pregnancy, 367-368 Acute limb ischemia, 166-167

Acute lung injury, 262 in idiopathic pulmonary fibrosis, 230 Acute phase reactants, in rheumatic disease, 821, 826 Acute respiratory distress syndrome. See Adult respiratory distress syndrome (ARDS). Acute stress disorder, 1080-1081 Acute tubular necrosis (ATN), 359, 360f. See also Acute kidney injury (AKI). clinical presentation of, 363 complications of, 363-364, 364t in hospitalized patients, 360-362, 362t outcome and prognosis in, 364 pathogenesis of, 365 in pregnancy, 368 prevention of, 364-365 in sepsis syndrome, 929 Adalimumab for Crohn disease, 437 for rheumatoid arthritis, 827, 827t for spondyloarthropathies, 832 ADAMTS-13, 558 therapeutic preparations of, 587 in thrombotic thrombocytopenic purpura, 331-332, 586-587 von Willebrand disease and, 575 Addison disease, 680-681, 683 Addisonian crisis, hypercalcemia in, 786-787 Adenocarcinoma breast, 610 esophagus, 410, 439, 606 gastric, 440-441 kidney, 612 lung, 266-267, 269, 603 of unknown primary, 615 Adenoma-to-carcinoma sequence, 596, 596f Adenosine as antiarrhythmic agent, 139 coronary blood flow and, 28-29 Adenosine deaminase deficiency, gene therapy for, 13 Adenosine diphosphate (ADP) inhibitors, 581-582, 581t. See also Clopidogrel. Adenosine stress testing, 55 with myocardial perfusion imaging, 57-58 Adenosine triphosphate (ATP) coronary blood flow and, 28-29 myocardial contraction and, 25, 26f Adhesive capsulitis, in diabetics, 881 Adie pupils, 1097 Adipocytokines, 631 Adipose tissue, secretory products of, 631 Adjuvant chemotherapy, 624 ADLs. See Activities of daily living (ADLs). Adolescent women’s health, 734-736 Adrenal glands, 679-690 anatomy of, 679, 679f future prospects for, 690b physiology of cortical, 679-680, 680f medullary, 689 Adrenal hyperplasia congenital, 683-684 primary aldosteronism secondary to, 177-178 Adrenal insufficiency, 680-683, 682t ACTH levels and, 664-665 in HIV-infected patients, 1025 hypoglycemia in, 724-725 in sepsis, 930-932 Adrenal medullary hyperfunction, 689-690. See also Pheochromocytoma. Adrenal tumors adenoma aldosterone-producing, 177-178, 689 cortisol-secreting, 688 carcinoma, 690 incidentaloma, 690 α2-Adrenergic agonists, perioperative, with noncardiac surgery, 279

1235

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Index

β-Adrenergic agonists, in asthma, 223-224 β2-Adrenergic agonists, in chronic obstructive pulmonary disease, 217-219 α-Adrenergic antagonists. See α blockers. β-Adrenergic antagonists. See β blockers. Adrenocortical hyperfunction, 684-689, 684t with glucocorticoid excess. See Cushing syndrome. with mineralocorticoid excess, 684t, 688-689, 688f Adrenocorticotropic hormone (ACTH), 660, 664-666, 679, 681f adrenal insufficiency and, 682-683 aldosterone and, 679-680 in congenital adrenal hyperplasia, 683-684 Cushing syndrome and, 684-685, 684t, 686f, 687-688 deficiency of, 662t, 665, 667 ectopic production of, 619t, 664-666, 684-685, 687-688 pituitary tumors secreting, 662t, 664-666 Adson test, 171 Adult respiratory distress syndrome (ARDS), 262 vs. cardiogenic pulmonary edema, 71 diffuse alveolar damage in, 236 in sepsis syndrome, 926f, 929 Advance directives, 1206 Afferent pupillary defect, 1096-1097, 1099 African Americans asthma in, management of, 223-224 constitutional neutropenia in, 536-537 end-stage renal disease in, 331 HIV-associated, 1026 focal segmental glomerulosclerosis in, 328 heart failure in, hydralazine and nitrates for, 72 hypertension in, 180 renal disease and, 175, 331, 350 in women, 746 sarcoidosis in, 231 African trypanosomiasis, 1038, 1039t Afterdepolarizations delayed, 119 early, 119 Afterload, 27-28, 28t Aging. See also Older adults. biology of, 1196-1198, 1197f, 1198t epidemiology of, 1196, 1197f frailty and, 1198, 1199f Agnosia, 1070 Agranulocytosis, stomatitis or pharyngitis in, 950 Air trapping, 208, 213, 220 Airway, anatomy of, 198, 199f Airway resistance, 201-202, 202f AKI. See Acute kidney injury (AKI). Akinetic-rigid syndrome, 1109, 1111t, 1112-1114 Alanine aminotransferase (ALT), 457-458, 457t. See also Aminotransferases. Albright hereditary osteodystrophy, 789 Albumin. See also Macroalbuminuria; Microalbuminuria. fatty acid transport with, 643 serum level of, 456, 457t hypocalcemia and, 790 protein status and, 638-639 Albuterol, in chronic obstructive pulmonary disease, 217-218 Alcohol abuse cancer risk and, 599 clinical manifestations of, 1221-1222 diagnostic criteria for, 1220, 1221t epidemiology of, 1220, 1221f hypoglycemia caused by, 723-724, 726 hypothermia in, 1083 Korsakoff syndrome in, 1076, 1224 liver disease caused by, 457-458, 471-472, 1221 cirrhosis, 471, 478 management of, 1222-1224 myoglobinuria in, 1190 organ damage in, 1221, 1222t pancreatitis and acute, 446, 450-451 chronic, 450-451 pharmacologic and metabolic factors in, 1220-1221 screening for, 1222-1223, 1223t sideroblastic anemia in, 522-523 tolerance in, 1220 withdrawal syndrome in, 1222 medical management of, 1224 xerophthalmia and xerostomia caused by, 857

Alcohol consumption absorption and metabolism in, 1220-1221 cardiovascular risk and, 97 cocaine with, 1230 by diabetic patient, 705 dilated cardiomyopathy caused by, 150-151 gout and, 865, 868 low-risk, 1223 osteoporosis and, 802 in pregnancy, 1224 triglycerides and, 646 Alcohol dependence, 1220-1221, 1221t Alcohol intoxication, acute, 1221-1222 Alcohol septal ablation, in hypertrophic cardiomyopathy, 152-153 Alcoholic fatty liver, 471-472 Alcoholic hepatitis, 457-458, 471-472 Alcoholic ketoacidosis, 318-319 Aldosterone, 679-680. See also Aldosteronism; Hyperaldosteronism, secondary; Hypoaldosteronism. adrenal insufficiency and, 682 hyperkalemia and, 312-313, 313f potassium secretion and, 294, 296-297 renin-angiotensin system and, 30, 679-680, 681f sodium reabsorption and, 294-295, 297 Aldosterone antagonists. See also Spironolactone. in heart failure, 72, 116-117 mechanism of action, 307-308, 308t Aldosterone resistance, 312-313 Aldosteronism. See also Hyperaldosteronism, secondary. glucocorticoid-remediable, 178, 321, 688-689 primary, 177-178, 177t, 184, 321, 684t, 688-689, 688f hypomagnesemia in, 794 Alemtuzumab for chronic lymphocytic leukemia, 548-549 human herpesvirus 6 encephalitis and, 943-944, 943t Alendronate for osteoporosis prevention and treatment, 807-809, 808t for Paget disease of bone, 814-816, 815t Alexia without agraphia, 1068 Alfuzosin, for benign prostatic hyperplasia, 754-755 “Alien hand” syndrome, 1113 Alimentary hypoglycemia, 725-727 Alkaline phosphatase leukocyte, 536 serum, 457-458, 457t in acute viral hepatitis, 468 hepatic abscess and, 975 jaundice and, 464 in Paget disease of bone, 812-813, 815-816 Alkalosis metabolic, 314, 314f, 320-321 in primary aldosteronism, 688 respiratory, 322 Allergic alveolitis. See Hypersensitivity pneumonitis. Allergic granulomatosis and angiitis. See Churg-Strauss syndrome. Allergic rhinitis, 945-946 Allergic sinusitis, 946 Alloimmune thrombocytopenia, 569-570, 570t Allopurinol before chemotherapy, 364-365, 367 for gout, 868, 868t for prevention of tumor lysis syndrome, 868-869 for uric acid stones, 342t, 343 Alosetron, for irritable bowel syndrome, 384-385 α blockers for benign prostatic hyperplasia, 754-755, 756t contraindications to, 181t-182t for kidney stone passage, 341 for prostatodynia, 758 side effects of, 181t-182t α-fetoprotein in hepatocellular carcinoma, 609, 621-622 in testicular cancer, 621-622, 766 Alport syndrome, 289, 330, 567 ALT. See Alanine aminotransferase (ALT). Alteplase, 112, 112t Alternative splicing, 3-4 Alveolar carbon dioxide equation, 199-200 Alveolar cyst disease, 1041

Alveolar ducts, 198, 199f Alveolar gas equation, 205 Alveolar oxygen equation, 200 Alveolar pressure, 200, 201f, 203-204, 203f Alveolar ventilation, 199-200 Alveoli, 198, 199f Alzheimer disease, 1072-1074, 1074t. See also Dementia. future prospects for, 1076b hippocampal degeneration in, 1070-1072 PET imaging in, 1057 Amanita phalloides poisoning, 4, 466 Amaurosis fugax, 1099, 1126-1127, 1130 Ambrisentan, for pulmonary hypertension, in systemic sclerosis, 848-849 Amebic abscess, hepatic, 975-976 Amebic dysentery. See Entamoeba histolytica infection. Amenorrhea, 740-741, 740t in anorexia nervosa, 635-636, 636t gonadotropins and, 666 primary, 735-736 prolactinoma with, 663 Amiloride, 307-308, 308t Amino acids, translation of code for, 3f-4f, 4 Aminoglycoside antibiotics mechanism of action, 4 nephrotoxicity of, 366, 368b ototoxicity of, 1103b 5-Aminosalicylic acid, for inflammatory bowel disease, 436, 436t Aminotransferases in hepatitis, 466 acute viral, 468, 468f alcoholic, 471 liver damage and, 457-458, 457t Amiodarone, 137t-138t, 138-139 epididymitis caused by, 768 vs. implantable cardioverter-defibrillators, 142-143 pulmonary toxicity of, 234-235, 235t Amitriptyline, for fibromyalgia syndrome, 876-877. See also Tricyclic antidepressants. Amlodipine in cardiomyopathy, 72 for Raynaud phenomenon, 847 Ammonia, serum, in liver disease, 456 Amnesia, 1070-1071, 1071t, 1075-1076 transient global, 1071, 1076 Amoxicillin–clavulanic acid, hepatotoxicity of, 472-473 Amphetamines, 1225t-1228t, 1229-1230 easily synthesized, 1229, 1230f heat stroke caused by, 1084 overdose of, 264t piperazines similar to, 1232-1233 treatment of abuse with, 1230 Ampulla of Vater, 488, 489f cancer of, 493-494 Amylase pleural fluid, 250 serum in acute pancreatitis, 448 in chronic pancreatitis, 451 Amylin, 631, 714 Amylin mimetics, 710t-713t, 714 Amyloid angiopathy, congophilic, 1132-1133 Amyloidosis autonomic dysfunction in, 1177-1178 factor X deficiency in, 576 glomerular disease in, 330-331 heredofamilial, 880 β2-microglobulin–associated, 880 neuropathy in, 1176t, 1181 primary (AL), 550, 550t, 553, 879-880 restrictive cardiomyopathy in, 153-154 rheumatic manifestations of, 879-880 secondary (AA), 880 Amyotrophic lateral sclerosis, 1171-1173 symptom management for, 1172-1173, 1173t symptoms and signs of, 1172, 1173t Anaerobic bacteria, 885-886 laboratory isolation of, 903 Anagrelide essential thrombocythemia and, 509-510, 585-586 for thrombocytosis, in polycythemia vera, 509 Anakinra, for rheumatoid arthritis, 827, 827t

Index Anal carcinoma, 607t, 609 in HIV-infected patients, 1021 Analgesic nephropathy, 334 Anaplasmosis, human granulocytic, 916-917 Anaplastic large cell lymphoma, 545 Anasarca, in constrictive pericarditis, 35 ANCA. See Antineutrophil cytoplasmic antibodies (ANCA). Andersen-Tawil syndrome, 1186t Androgen deficiency. See Hypogonadism, male. Androgen deprivation therapy, 765, 765t Androgen excess, in congenital adrenal hyperplasia, 683-684 Androgen insensitivity, 693, 735-736 Androgen synthesis adrenal, 679f-680f, 680 ovarian, 733 Anemia, 520-532. See also Aplastic anemia; Hemolytic anemia. chemotherapy-induced, 627 of chronic disease, 522-523, 526 in chronic kidney disease, 374, 376 clinical approach to, 520-522 clinical presentation of, 520 definition of, 520 differential diagnosis of, 521f, 522t, 526t in hypothyroidism, 676 of inflammation, 526 laboratory evaluation of, 520-522, 522f, 522t pernicious, 524-525 in systemic lupus erythematosus, 835, 837t in ulcerative colitis, 431 Anesthesia, cardiac complications and, 279-280 Anesthetic agents hepatotoxicity of, 473 malignant hyperthermia caused by, 1188 Aneurysm(s) aortic, 167-170, 167f, 167t in giant cell arteritis, 862 throat pain caused by, 950 coronary artery, in Kawasaki disease, 861 intracranial, 1133-1134, 1133f aortic coarctation with, 79-80 hypertensive hemorrhage and, 1132 imaging of, 1134 in infective endocarditis, 1162-1163 in polycystic kidney disease, 338 rupture of, 1134. See also Subarachnoid hemorrhage. mycotic, 962, 967, 1133, 1162-1163 ventricular, 116, 143 Angina pectoris, 98-106. See also Myocardial ischemia. aortic regurgitation with, 87 aortic stenosis with, 84 clinical presentation of, 99, 99t sore throat in, 950 coronary artery bypass grafting for, 104-105, 158-159 evaluation of, 99-102, 100f-101f, 102t medical management of, 99t, 102-104, 103t microvascular disease and, 98 pain of, 32-33, 33t, 99 vs. esophageal pain, 409 pathophysiology of, 98 plasminogen activator inhibitor-1 in, 580-581 revascularization for, 104-105 risk factor modification for, 102, 102t severe refractory, 105 unstable. See Unstable angina. variant. See Variant (Prinzmetal) angina. in women, 745 Anginal equivalent, dyspnea as, 33 Angiogenesis, induced by tumor cells, 594, 615 Angiogenesis inhibitors, 594, 625, 626t for hepatocellular carcinoma, 484-485 Angiography. See also Computed tomographic angiography (CTA); Magnetic resonance angiography (MRA). coronary. See Coronary angiography. in gastrointestinal bleeding, 388, 406 intracranial, 1056 of aneurysms, 1134 of tumors, 1155 pulmonary, 197, 211 in pulmonary embolism, 242-243, 242f

Angiography (Continued) renal, 303 in renal artery stenosis, 347 visceral, 406 Angioma, cavernous, 1134 Angiomyolipoma, renal, 340 Angioplasty, percutaneous transluminal in Budd-Chiari syndrome, 486 coronary, 96f, 104-105. See also Percutaneous coronary intervention (PCI). noncardiac surgery and, 277 renal artery for atherosclerotic stenosis, 347-348 for fibromuscular dysplasia, 177, 348 Angiotensin I, 30, 188, 679-680, 681f Angiotensin II, 30, 188, 297, 679-680, 681f Angiotensin receptor blockers in chronic kidney disease, 369-371 contraindications to, 181t-182t in coronary artery disease, 102-103 in heart failure, 72 for hypertension, 179-180, 179t-180t, 182-183 in renal artery stenosis, 346 perioperative discontinuation of, 279 for Raynaud phenomenon, 847 side effects of, 181t-182t Angiotensin-converting enzyme (ACE), 30, 679-680, 681f elevated, in sarcoidosis, 232 Angiotensin-converting enzyme (ACE) inhibitors adverse effects of, 181t-182t renal, 366 in chronic kidney disease, 369-371 contraindications to, 181t-182t in coronary artery disease, 102-103 in diabetes, with coronary artery disease, 102-103 in heart failure, 72 after myocardial infarction, 114-115 for hypertension, 179-180, 179t-180t, 182-183 in renal artery stenosis, 346 after stroke, 1132 in hypertensive urgencies, 185 after myocardial infarction in heart failure, 114-115 ST-segment elevation, 111 perioperative discontinuation of, 279 in pregnancy, 739, 739t for scleroderma renal crisis, 352, 846, 848 Angiotensinogen, 679-680, 681f Animal bites, osteomyelitis secondary to, 988, 988t Animal exposure febrile syndromes associated with, 912t, 913-914 pneumonia associated with, 952t Anion gap, 317, 317t in metabolic acidosis, 317-318, 318t in chronic kidney disease, 369, 375 urinary, 299-300, 318 Anisocoria, 1096, 1098f Anistreplase, 112 Ankle-brachial index, 64-65, 165-166, 166t Ankylosing spondylitis, 829 clinical features of, 830-833, 830t epidemiology of, 829 inflammatory bowel disease with, 434 pathogenesis and pathophysiology of, 829-830 radiographic features of, 831-832 treatment of, 832-833 Anorchia, bilateral, 692-693 Anorexia nervosa, 635-637, 636t refeeding in, 793 Anosmia, in Kallmann syndrome, 692 ANP. See Atrial natriuretic peptide (ANP). Antabuse. See Disulfiram (Antabuse). Antacids in critically ill patients, 418 in gastroesophageal reflux disease, 410, 410t hypermagnesemia caused by, 793 in peptic ulcer disease, 423 Anterior cerebral artery, stroke associated with, 1127, 1127t Anterior horn cells, 1172t. See also Lower motor neuron diseases. Anthracyclines, dilated cardiomyopathy caused by, 150 Anthrax, 913, 1044-1046 Antiandrogens, 765

1237

Antiarrhythmic agents, 136-139 adenosine used as, 139 in asymptomatic arrhythmias, 136 atropine used as, 139 classification of, 136, 136t class I, 136-138, 136t class II, 136t, 138 class III, 136t, 138-139 class IV, 136t, 138 commonly used agents characteristics of, 137t side effects of, 138t digoxin used as, 139 general guidelines for use of, 136 for ventricular tachycardia, after myocardial infarction, 113 Antibiotic prophylaxis of bacterial meningitis, 936 in cirrhotic ascites, 482-483 of endocarditis. See Infective endocarditis, antibiotic prophylaxis of. in neutropenic patients, 1032-1033 of rheumatic fever, 92, 948 of traveler’s diarrhea, 984, 1036 of urinary tract infection, 991 Antibiotic therapy. See Antimicrobial therapy. Antibodies. See also Autoantibodies; Immunoglobulin(s). diversity of, 894 in host response, 895-896 antiviral, 897 T lymphocytes and, 892-893 immunodeficiency with respect to, 1029-1030 properties of, 892, 892t serum levels of, 899-900 structures of, 894, 894f Anticardiolipin antibodies, 356, 356t, 585, 841 in systemic lupus erythematosus, 835, 837-838 testing for, 587, 842, 842t thrombocytopenia with, 568-569 Anticholinergic agents in chronic obstructive pulmonary disease, 217-218 for irritable bowel syndrome, 384-385 Anticholinesterase test, 1191-1192 Anticholinesterases, for myasthenia gravis, 1192 Anticoagulants, endogenous, 560-561, 561f inherited deficiency of, 582t, 583-584 Anticoagulation. See also Heparin; Warfarin. after acute coronary syndrome, 116-117 in acute limb ischemia, 166-167 in antiphospholipid antibody syndrome, 842-843 in atrial fibrillation, 126-127, 1128-1130 during breastfeeding, 590 in Budd-Chiari syndrome, 486 in cancer patient, hospitalized, 616 for cerebral venous sinus thrombosis, 1131-1132 for deep venous thrombosis, 171 in heart failure, 73 in heparin-induced thrombocytopenia, 586 in mitral stenosis, 89 perioperative, 590 for portal vein thrombosis, 486 in pregnancy, 590 with prosthetic heart valves, 92-93 noncardiac surgery and, 281 in pregnancy, 163 in pulmonary arterial hypertension, 170 in pulmonary embolism, 173, 243 for renal vein thrombosis, 357 in spinal cord injury, 1139-1140 in stroke patient, 1130 for stroke prevention primary, 1128-1130 secondary, 1132 venous hemostasis and, 555 for venous thromboembolism, 587-590, 588t-589t Anticodon, 3f-4f, 4 Anticonvulsants. See Antiepileptic drugs. Anticyclic citrullinated peptide antibodies, in rheumatoid arthritis, 824, 826 Antidepressants, 1079t. See also Tricyclic antidepressants. in anxiety disorders, 1081 in fibromyalgia syndrome, 876-877

1238

Index

Antidepressants (Continued) in narcolepsy, 1066 in somatoform disorders, 1082 Antidiabetic agents, 708, 710t-713t. See also specific drug classes. Antidiarrheal agents, 984, 1036 in inflammatory bowel disease, 437 Antidiuretic hormone (ADH), 30. See also Desmopressin (DDAVP); Vasopressin. cardiovascular effects of, 667 diabetes insipidus and, 311 inappropriate secretion of, 309-311, 310t, 619t pituitary gland and, 660, 667-669 renal transport and, 292-296, 293f, 667 water balance and, 305-306, 308-309, 309f Antiemetic agents, with cancer chemotherapy, 627 Antiepileptic drugs, 1149-1150 in brain tumor patients, 1156 breastfeeding and, 1152 discontinuing, 1153 hepatotoxicity of, 473 hypocalcemia caused by, 790 for migraine prevention, 1088, 1090t for neuropathic pain, 1178t in postpartum period, 1152 in pregnancy, 739, 739t, 1151-1152 teratogenicity of, 1151-1152 Antiepileptic hypersensitivity syndrome, 473 Antifungal agents, 906t-908t, 908-909 for febrile neutropenic patients, 1032-1033 Antigen-presenting cells, 892, 895-896, 895f Antiglomerular basement membrane disease, 237, 323f, 327 Antihypertensive agents, 179, 179t-180t after acute coronary syndrome, 116-117 for acute severe hypertension, 184-185, 185t in African Americans, 180 in chronic kidney disease, 370 contraindications and side effects of, 181t-182t in coronary artery disease, 182 in diabetic patients, 182, 719 for high-cardiovascular-risk patients, 180 in hypertensive emergencies, 185, 185t in hypertensive nephrosclerosis, 182 in hypertensive urgencies, 185 in isolated systolic hypertension, 182-183 lifetime benefit of, 186 in pregnancy, 184, 352, 352t for resistant hypertension, 184 after stroke, 183 in uncomplicated hypertension, 179-180 Antimalarial medications, 1035-1037. See also Chloroquine. for systemic lupus erythematosus, 838 Antimicrobial resistance choice of drug and, 904 testing for, 901-902, 909 Antimicrobial therapy, 904-909. See also Antibiotic prophylaxis; specific infections. antifungal agents in, 906t-908t, 908-909 for febrile neutropenic patients, 1032-1033 antiviral agents in, 906t-908t, 908 liver damage caused by, 472-473 prophylactic, in neutropenia, 1032-1033 broad-spectrum, 904 combinations of drugs in, 908 drug characteristics and, 905, 906t-908t duration of therapy and, 905-908 empirical, 904, 908 in septic patients, 930, 931t future prospects for, 909b inhibition of transcription by, 4 inhibition of translation by, 4 liver damage caused by, 472-473 monitoring of, 908 pathogen identification and, 904 resistance testing in, 901-902, 909 route of administration and, 905 selectivity of agents in, 904 site of infection and, 904-905 toxic effects of, 905, 908 Antimicrosomal antibodies, 671-672 Antimitochondrial antibodies, 881

Antineutrophil cytoplasmic antibodies (ANCA) diffuse alveolar hemorrhage and, 235-236 low diagnostic significance of, 820-821 in Sjögren syndrome, 855-856 in systemic lupus erythematosus, 835-836, 837t in ulcerative colitis, 433 vasculitides associated with, 859-860 leukocytoclastic, 862 pulmonary involvement in, 235-237 renal involvement in, 327 Antioxidants, post–myocardial infarction patients and, 116-117 Antiphospholipid antibody syndrome, 332, 356, 356t, 841-843 catastrophic, 842-843 clinical features of, 841-842 diagnosis of, 587, 589, 842, 842t future prospects for, 843b management of, 842-843 pathogenesis of, 841 pregnancy and, 590, 841-843, 842t in systemic lupus erythematosus, 838 thrombocytopenia in, 568-569, 841-842 thrombosis in, 585, 841-842, 842t Antiplatelet therapy, 581-582, 581t. See also Aspirin; Clopidogrel; Glycoprotein IIb/IIIa inhibitors. after acute coronary syndrome, 116-117 arterial hemostasis and, 555 for carotid stenosis, 1130 in coronary artery disease, 102-103 in non–ST-segment elevation myocardial infarction, 108-110 perioperative, with noncardiac surgery, 279 in stroke, 1130 for stroke prevention, 1132 after transient ischemic attack, 1130 in unstable angina, 108-110 Antipsychotic medications, 1081 Antisense strand, 3 Antisynthetase syndrome, 850-853, 851t Antithrombin, 560-561 assay for, 587 deficiency of, 582t, 583-584 Antithrombotic therapy. See also Anticoagulation; Antiplatelet therapy. in non–ST-segment elevation myocardial infarction, 108-110 in unstable angina, 108-110 Antithymocyte globulin for aplastic anemia, 502 aseptic meningitis associated with, 943-944, 943t for myelodysplastic syndrome, 505-506 Antithyroid drugs, 673 α1-Antitrypsin deficiency biliary neoplasms in, 493-494 bronchiectasis in, 220 emphysema in, 215-216 liver disease in, 474-475 Antiviral agents, 906t-908t, 908 liver damage caused by, 472-473 prophylactic, in neutropenia, 1032-1033 Anton syndrome, 1099 Anxiety disorders, 1079t-1080t, 1080-1081 in epilepsy, 1152-1153 in older adults, 1202-1203 Anxiety states chest pain in, 34t palpitation in, 33-34 vs. seizure, 1148 Aorta age-related stiffening of, 182-183 intramural hematoma of, 168, 348 pressure in, 27f, 27t Takayasu arteritis of, 169 trauma to, 157-158 Aortic aneurysm, 167-170, 167f, 167t in giant cell arteritis, 862 throat pain caused by, 950 Aortic coarctation, 78t, 79-80, 80f hypertension secondary to, 177t noncardiac surgery in patient with, 282 Aortic dissection, 168, 168f, 348-350, 349f acute pain of, 33, 33t in pregnancy, 164 of Marfan syndrome patient, 163

Aortic regurgitation, 85-87, 86t acute, 87 bicuspid aortic stenosis with, 78 carotid pulse associated with, 36-38, 38f infective endocarditis complicated by, 966 noncardiac surgery in patient with, 281 Aortic root enlargement bicuspid aortic valve with, 78 in Marfan syndrome, β blockers and, 167-168 Aortic stenosis, 84-85, 85f, 86t carotid pulse associated with, 36-38, 38f congenital, 77-79, 78t, 84-85 supravalvular, 78-79 noncardiac surgery in patient with, 162, 281 pregnancy in patient with, 163 Aortic ulcer, penetrating, 168, 169f Aortic valve. See also Aortic regurgitation; Aortic stenosis. anatomy of, 22 fibroelastoma of, 156 opening of, 27f Aortic valve repair, percutaneous, 74b Aortic valve replacement for regurgitation, 87 for stenosis, 85 Aortitis in giant cell arteritis, 862 in spondyloarthropathies, 831 syphilitic, 1001 Aphasia, 1068-1070, 1070t, 1071f Aphthous esophagitis, in HIV-infected patients, 1021, 1021t Aphthous stomatitis, 947 in HIV-infected patients, 1021 Aplastic anemia, 500-502, 501t acute viral hepatitis with, 470 stomatitis or pharyngitis in, 950 Aplastic bone disease, 798-799 Aplastic crisis, in sickle cell disease, 530 Apnea definition of, 245, 1064-1065 types of, 1064-1065 Apneustic breathing, 246 Apolipoprotein(s), 643-644, 644f, 644t Apolipoprotein B-100, 643, 644f, 644t familial defective, 648 Apolipoprotein C-II, 643, 644f, 644t deficiency of, 650 Apolipoprotein E, 643, 644f, 644t mutations of, 649 Apoptosis, resistance to, in tumor cells, 594, 624-625 Apraxia, 1070, 1071f Aprotinin, 580-581 APSAC (anisoylated plasminogen streptokinase activator complex), 112 Aquaporin-2 channels, 482 Aquaretics, 482 ARDS. See Adult respiratory distress syndrome (ARDS). Argatroban, in heparin-induced thrombocytopenia, 586 Arginine vasopressin. See Vasopressin. Argyll-Robertson pupils, 1097 Aristolochic acid, 335, 371-372 Aromatase inhibitors, for breast cancer, 626-627 Arrhythmias, 118-144. See also Bradyarrhythmias; Tachyarrhythmias. classification of, 120 clinical presentation of, 131 clinical syndromes of, 143-144, 143t diabetic neuropathy and, 718 evaluation of, 131-133, 132f, 132t future prospects for, 144b in hypertrophic cardiomyopathy, 152 in hypokalemia, 313-314 management of, 135-136. See also Antiarrhythmic agents. mechanisms of, 119-120, 120f after myocardial infarction, 113-114, 113t noncardiac surgery in patient with, 162, 281 palpitation associated with, 33-34 premature beats, 120-122, 121f in sarcoidosis, 232-233 in sleep apnea, 245-246 sudden death caused by. See Sudden cardiac death.

Index Arrhythmias (Continued) syncope secondary to, 131, 133-134, 133t in systemic sclerosis, 846, 848t, 849 trauma-associated, 157 tumor-induced, 156 Arrhythmogenic right ventricular cardiomyopathy/ dysplasia, 149, 150t, 154-155 Arsenic trioxide, for acute promyelocytic leukemia, 517 Artemisinin, 1037 Arterial embolism acute lower limb ischemia in, 166-167 cardioembolism, stroke caused by, 1125, 1125t, 1128-1130 renal artery obstruction in, 350 Arterial infections, 967-968 Arterial pressures, in normal cardiac cycle, 26-30, 27f, 27t Arterial pulses, 36-38, 38f Arterial switch procedure, 81 Arterial thrombosis in antiphospholipid antibody syndrome, 841 antithrombin deficiency and, 583 in atherosclerotic setting, 580-582, 587 cancer-associated, 616 coronary. See Coronary thrombosis. in essential thrombocythemia, 585-586 heparin-induced, 586 laboratory evaluation of, 587 lower limb ischemia caused by, 166-167 perioperative care and, 590 protein C or S deficiency and, 583-584 risk factors for, 580, 582t in systemic lupus erythematosus, 835 Arteriography. See Angiography. Arterionephrosclerosis, hypertensive, 336 Arteriovenous fistula, 169-170 Arteriovenous malformation, 169-170 central nervous system, 1134-1135 Arteritis coronary, 97-98 giant cell. See Giant cell arteritis. Takayasu, 169, 350, 859f, 861 temporal, 169, 859f, 861-862, 1092 Arthritis. See also Osteoarthritis; Psoriatic arthritis; Reactive arthritis; Rheumatoid arthritis; Septic arthritis; Spondyloarthropathy(ies). acute monoarticular or oligoarticular, 985 in amyloidosis, 879-880 crystal-induced, 818, 820f, 864-869. See also Gout. differentiating features of types of, 819t evaluation of, 818-822 biopsy in, 821 history and examination in, 818-820, 819t, 820f laboratory testing in, 820-821, 821t radiographic studies in, 821 summary of, 822 in hyperparathyroidism, 882 infective, 985-987, 986t. See also Septic arthritis. kidney disease and, 298 in Lyme disease, 917 malignancy-associated, 878 in Paget disease of bone, 812, 814, 816 in sarcoidosis, 882 in sickle cell disease, 879 in systemic lupus erythematosus, 835, 837t viral, 826, 985-986, 986t in Whipple disease, 880 Arthritis mutilans, 831-832 Arthrocentesis. See Synovial fluid analysis. Asbestos lung cancer and, 266, 603 mesothelioma and, 250-251 Asbestosis, 226, 227f, 228t-229t, 237-238 Ascaris infection, 1039, 1040t Aschoff bodies, 92 Ascites causes of, 481, 482t cirrhotic, 479, 480f, 481-482, 482f in constrictive pericarditis, 35 in heart failure, 35, 69-70 peritonitis associated with, 977 refractory, 482 Aspartate aminotransferase (AST), 457-458, 457t. See also Aminotransferases.

Aspergillosis, 888 allergic bronchopulmonary, 193, 220-221, 240, 888 in asthma, 223 in cystic fibrosis, 221 chronic sinusitis in, 946 disseminated, 1031-1032 pneumonia in, 1032 pulmonary infiltrates in, 1031, 1032f Aspirin after acute coronary syndrome, 116-117 in antihypertensive regimen, 180 in antiphospholipid antibody syndrome, 842-843 antiplatelet mechanism of, 559, 581-582 clopidogrel with, 581-582 after coronary artery bypass graft, 105 in coronary artery disease, 102-103 for diabetic patients, 704, 719 for Kawasaki disease, 861 in myocardial infarction, 110-111 non–ST-segment elevation, 109-110 with thrombolytic therapy, 112-113 peptic ulcer disease and, 420 perioperative, with noncardiac surgery, 279 in peripheral arterial disease, 166 platelet dysfunction caused by, 572-573, 572t with prosthetic heart valves, 92-93 after stent implantation, 104-105 for stroke prevention primary, 1128-1130 secondary, 1132 in systemic lupus erythematosus, 837-838 for thromboembolism prophylaxis, in pregnancy, 590 for thrombosis, in myeloproliferative disorders, 585-586 for unstable angina, 109-110 Assisted living facilities, 1207 Assisted suicide, 1216 AST. See Aspartate aminotransferase (AST). Asterixis, 194-195, 1111t Asthma, 190-191, 213, 214f, 214t, 222-224 Churg-Strauss syndrome associated with, 236-237, 860 clinical manifestations of, 223 cough in, 193 nocturnal dyspnea in, 192 wheezing in, 192-193, 195 COPD overlapping with, 213-214, 222-223 diagnostic studies in, 223, 223t bronchoprovocation testing, 209, 209f, 223 exercise-induced, 192, 222 management of, 218f, 223-224 pathogenesis of, 222 physical examination in, 194-195 prevalence of, 190, 222 Astrocytoma, 1154, 1157 anaplastic, 1156 Ataxias, 1111t, 1116-1117, 1117t Ataxic breathing, 246 Ataxic dysarthria, 1111t, 1116 Atelectasis in acute respiratory distress syndrome, 262 physical findings in, 196t Atherosclerosis accelerated, in rheumatoid arthritis, 825-826 optic neuropathy in, 1099 pathophysiology of, 95-96, 643-644 peripheral, 165-167, 166f, 166t renal artery stenosis in, 177, 178f, 346-348, 347f risk factors for, 96-97, 96t stroke caused by, 1125, 1126f Atherosclerotic plaques disruption of, 95, 97 infection of, 968 Atherothrombosis, 580-582, 587. See also Arterial thrombosis. Athetosis, 1111t ATN. See Acute tubular necrosis (ATN). Atonic seizure, 1146 Atorvastatin, in antihypertensive regimen, 180 Atovaquone-proguanil for malaria, 1037 for malaria prophylaxis, 1035-1036 ATP. See Adenosine triphosphate (ATP). Atrial abnormalities, electrocardiography in, 50, 50t

1239

Atrial diastolic gallop, 41 Atrial fibrillation, 125f, 126-127, 127f cardioversion for, 141 future prospects for, 144b in hyperthyroidism, 882 in hypertrophic cardiomyopathy, 153 jugular venous pulse and, 36, 37f after myocardial infarction, 113-114 radiofrequency catheter ablation for, 126-127, 127f, 142 stroke prevention in, 1128-1130, 1132 in Wolff-Parkinson-White syndrome, 128f, 129-130 Atrial flutter, 125-126, 125f bypass tracts and, 129-130 cardioversion for, 141 Atrial natriuretic peptide (ANP) in heart failure, 69 renal sodium transport and, 295, 306 Atrial premature complexes, 120-121, 121f Atrial pressures left, 26-27, 27f, 27t right, 26-27, 27t, 36 Atrial septal defects, 75-77, 76f, 76t Ebstein anomaly with, 79 Atrial tachyarrhythmias, 124-127, 125f, 127f bypass tracts and, 128f, 129 direct current cardioversion for, 141 Atrial tachycardia, 124-125, 125f Atrioventricular block, 122-123, 124f jugular venous pulse in, 36, 37f in myocardial infarction, 114 noncardiac surgery in patient with, 162 Atrioventricular nodal re-entrant tachycardia, 127-128, 128f, 142 Atrioventricular nodal (junctional) tachyarrhythmias, 127-129, 128f Atrioventricular node, 24, 24f action potential in, 118 autonomic influences on, 24-25, 118 Atrioventricular re-entrant tachycardia antidromic, 129 orthodromic, 128f, 129 Atrioventricular septal defect, 75 Atrophy, in neuromuscular diseases, 1172t, 1183 Atropine, as antiarrhythmic agent, 139 Auditory dysfunction, 1100-1103, 1100f-1101f, 1100t future prospects for, 1103b in older adults, 1203 Auer rods, 513, 517 Augmented leads, 47-48 Aura of migraine, 1087-1088, 1149 of seizures, 1143, 1149 Auscultation, 39-45. See also Murmurs. abdominal, 383 abnormal heart sounds in, 40-42, 41t, 42f in acute coronary syndrome, 106 in angina episode, 99 in arrhythmia evaluation, 131 in atrial fibrillation, 126 with atrial septal defect, 76, 76t with bicuspid aortic stenosis, 78 computer technology for, 45b in dilated cardiomyopathy, 151 in heart failure, 70 in hypertrophic cardiomyopathy, 152 of lungs, 194t, 195 in mitral stenosis, 88 in mitral valve prolapse, 90-91 normal heart sounds in, 39-40 pericardial rub in, 44, 145 prosthetic heart sounds in, 44-45 in pulmonary arterial hypertension, 170 in pulmonary embolism, 172 in pulmonic valve stenosis, 78t, 79 technique of, 39, 40t in tricuspid regurgitation, 91 in tricuspid stenosis, 91 in valvular heart disease, acquired, 86t with ventricular septal defect, 76t, 77 Auscultatory gap, 174 Austin Flint murmur, 43-44, 87 Autism spectrum disorders, 1120-1121

1240

Index

Autoantibodies. See also Anticardiolipin antibodies; Antineutrophil cytoplasmic antibodies (ANCA); Antiphospholipid antibody syndrome. anticyclic citrullinated peptide, in rheumatoid arthritis, 824, 826 anti-β2-glycoprotein I, 585, 587, 841-842, 842t antimicrosomal, 671-672 antimitochondrial, 881 anti-myeloperoxidase, 235-237, 327, 860 anti-proteinase-3, 235-236, 327, 860 in autoimmune hemolytic anemia, 527 in glomerular diseases, 324-325, 327 in idiopathic myositis, 850, 851t to insulin, 725 platelet-associated, 568 to thyroglobulin, 671-672, 674 TPO Ab (thyroid peroxidase), 671-672, 674, 676 to TSH receptor, 671-673 Automatic junctional tachycardia, 128-129, 128f Automaticity, 118 abnormal, 119 enhanced, 119 Automatisms, 1143, 1145-1146, 1151 Autonomic nervous system cardiac impulses and, 24-25, 118 coronary artery innervation by, 29 renal innervation by, 286 Autonomic neuropathy, diabetic, 718, 760, 1180 Autosomal dominant disorders, 11t, 12 Autosomal recessive disorders, 11t, 12 Avascular necrosis of bone, 988 Avian influenza, 913, 955, 1036-1037 Axonal neuropathies, 1175-1178 Charcot-Marie-Tooth type 2, 1181 in critical illness, 1180 toxic-induced, 1180 5-Azacytidine mechanism of action, 596 for myelodysplastic syndrome, 505 Azathioprine for idiopathic pulmonary fibrosis, 230 for inflammatory bowel disease, 436-437 for myasthenia gravis, 1192 for rheumatoid arthritis, 827 for systemic lupus erythematosus, 838 Azithromycin, for bronchiolitis obliterans syndrome, 220 B B lymphocytes, 539 antigenic diversity and, 893-894, 896 development of, 539, 540f in lymphoid follicles, 540 peripheral blood, 540-541 in rheumatoid arthritis, 824, 824t, 825f B rings, 412 Babesia microti, 889t, 1039t Bacillary angiomatosis, in HIV-infected patients, 1020t Bacillus cereus infection, food-borne, 980 Bacillus species, 886 Back pain, 1093-1095, 1094f, 1094t-1095t Backwash ileitis, 435-436 Bacteremia. See also Blood cultures; Septicemia. in fever of unknown origin, 921 nosocomial, 995 Bacteria classification of, 885-888 host defenses against, 896-897 laboratory isolation of, 902-903 Bacterial overgrowth, small bowel, 393-395, 398 in chronic pancreatitis, 452 Bactericidal antibiotics, 904-905 Bacteriostatic antibiotics, 904-905 Bacteriuria asymptomatic, 990 definition of, 989-990 Bacteroides fragilis, 886 Baker cyst, 824 Ballism, 1109, 1111t Balloon pump. See Intra-aortic balloon pump (IABP). Balloon valvuloplasty for aortic stenosis, 85 for mitral stenosis, 89

Balloon-assisted enteroscopy, 402 Balsalazide, for inflammatory bowel disease, 436 Barbiturates. See also Phenobarbital. abuse of, 1224-1225, 1225t-1228t, 1228 to induce coma, 1137 Bariatric surgery, 395, 632t, 633-634, 633f, 705 Barium contrast studies, 405, 405f colorectal cancer and for diagnosis, 442 for screening, 442-443, 443t dyspepsia and, 425 esophageal, 405, 411, 412f of gastric malignancies, 441 in gastrointestinal bleeding, 388 in malabsorption, 391 of small intestine, 391, 394 Barium enema, 405. See also Barium contrast studies. Baroreceptors, 29-30 vagal tone and, 118 water balance and, 305-306, 308-309, 309f Barrett esophagus, 403f, 410, 439, 606 Bartonella henselae infection, 919-920 Bartonella species, 886 Bartter syndrome, 292-293, 314-316, 315t, 321 Basal cell carcinoma, 614 Basal energy expenditure, 639 Basal ganglia, 1108-1109, 1110f-1111f, 1110t hemorrhage in, 1132, 1133t primary dystonias and, 1114 toxic parkinsonism and, 1114 Toxoplasma abscesses in, 1159 vascular parkinsonism and, 1114 Basilar artery, 1123-1124, 1124f migraine associated with, 1149 occlusion of, 1127 Basophils, 534-535, 534f progenitors of, 498, 498f Becker myotonia congenita, 1186t, 1187 Behavior therapy. See Cognitive behavioral therapy. Behçet syndrome, oral ulcerations in, 947 Bence Jones protein, in multiple myeloma, 551 Benign paroxysmal positional vertigo, 1104-1105, 1105t, 1106f Benign prostatic hyperplasia (BPN), 752-756, 756t Benzodiazepines abuse of, 1224-1228, 1225t-1228t for alcohol withdrawal, 1224 for epilepsy, 1149-1151 for status epilepticus, 1152t Bernard-Soulier syndrome, 572t, 573 Bernoulli equation, modified, 55-56 Berry aneurysms, 1133, 1133f Berylliosis, 225-226, 228t-229t, 231, 238 β blockers for angina pectoris, 103-104, 103t for aortic root enlargement, in Marfan syndrome, 167-168 for aortic ulcer or hematoma, 168 for arrhythmias, 138-139, 138t contraindications to, 181t-182t in diabetic patients for hypertension, 719 hypoglycemia caused by, 724 in heart failure, 73 in dilated cardiomyopathy, 151 for hypertension, 179-180, 179t-180t, 182 in diabetic patients, 719 with peripheral arterial disease, 166 in pregnancy, 352 in hypertrophic cardiomyopathy, 152 for long QT syndrome, 143 after myocardial infarction, 142-143 in myocardial infarction non–ST-segment elevation, 108-109 ST-segment elevation, 111 perioperative, with noncardiac surgery, 161-162, 277-279 selectivity of, 103-104 side effects of, 181t-182t in thyrotoxicosis, 673 in unstable angina, 108-109 in variant angina, contraindication to, 106 for variceal prophylaxis, 481, 486, 487b

Bevacizumab, 594, 625, 626t for lung cancer, 269 for renal cell carcinoma, 612 Bezold-Jarisch reflex, 114 Bicarbonate acid-base assessment and, 317, 317t for acidosis, 318-319 in chronic kidney disease, 375 carbon dioxide transported as, 204 in chronic pancreatitis, 450-451 in diarrhea, 396-397 duodenal secretion of, 414-415 esophageal secretion of, 409 fluid compartments and, 305, 306f gastric secretion of, 415-416, 419-420 hydrogen ion excretion and, 316-317 intestinal transport of, 396-397 in metabolic acidosis, 317-318, 318t in metabolic alkalosis, 320-321 renal reabsorption of, 292, 294-295, 316-317 in renal tubular acidosis, 319-320, 319f-320f in respiratory acidosis, 321-322 Bicuspid aortic valve, 77-79, 84 aortic coarctation with, 79-80 regurgitation with, 85-87 Bifid scrotum, 693 Biguanides, 709-712, 710t-713t Bile, 488 Bile acid sequestrants, 647, 647t Bile acids, 488, 643 Bile salt resin binders, 437 Bile salts, 389 deficiency of, 390, 394 malabsorption of in Crohn disease, 432 resin binders for, 437 Biliary colic, 490-492 Biliary neoplasms, 493-494. See also Cholangiocarcinoma. Biliary obstruction, 493 jaundice in, 461t, 463-464 tests of, 456-458, 457t Biliary strictures, 493 Biliary tract anatomy of, 488, 489f endoscopy of, 402-403 inflammatory bowel disease and, 435 magnetic resonance imaging of, 406 physiology of, 488 Bilirubin. See also Hyperbilirubinemia. laboratory measurement of, 460 metabolism of, 460, 462f serum levels of, 457-458, 457t in alcoholic hepatitis, 471 hepatic abscess and, 975 normal, 460 in pneumococcal pneumonia, 953 Binge drinking, 1220, 1221f Binswanger disease, 1074 Biologic response modifiers for cancer, 627 for chronic inflammatory disorders, 13 for rheumatoid arthritis, 827, 827t Biomarkers, cancer, 621-622 Biot respiration, 246 Bioterrorism, 1044-1049, 1046t agents in anthrax, 1044-1046 botulinum toxin, 1045, 1048 categories of, 1044, 1045t plague, 1047-1048 smallpox, 1046-1047, 1047f viral hemorrhagic fevers, 1048 definition of, 1044 future prospects for, 1049b history of, 1044-1046 Bipolar disorder, 1079-1080 Bisferious pulse, 36-38, 38f Bismuth subsalicylate, for traveler’s diarrhea, 984, 1036 Bisoprolol, in heart failure, 73 Bisphosphonates for hypercalcemia, 618, 618t in metastatic breast cancer, 610

Index Bisphosphonates (Continued) for osteoporosis prevention and treatment, 807-808, 808t for Paget disease of bone, 814-816, 815t Bites, osteomyelitis secondary to, 988, 988t Biventricular pacing, for heart failure, 68 Bladder imaging of, 302-303, 611 infection of, 989-991 Bladder cancer, 611-612, 611t Bladder outlet obstruction, benign prostatic hyperplasia with, 752-754 Blast crisis, in chronic myelogenous leukemia, 511-512 Blastomyces dermatitidis, 888 Bleeding, 564-579. See also Hemorrhage. clinical evaluation of, 564-565, 565f, 565t coagulation factor disorders and, 565f, 576-577, 576t fibrinogen disorders and, 575-579 future prospects for, 579b gastrointestinal. See Gastrointestinal bleeding. in liver disease, 577 fulminant hepatic failure, 476-477, 477t major disease categories with, 565 with normal laboratory screen, 565f, 577-579 platelet count and. See Thrombocytopenia. platelet dysfunction and, 566-572, 572t. See also von Willebrand disease. transfusion therapy for. See Platelet transfusion; Transfusion. in uremia, 374 urinary tract. See Hematuria. vascular causes of, 565-566 Bleeding time, 556-557, 564, 565f Bleomycin pulmonary toxicity of, 234-235, 235t scleroderma-like effects of, 847t Blepharospasm, 1115t Blindness. See also Visual loss. acute transient monocular, 1099 cortical, 1099 Blood and body fluids, standard precautions for, 992, 1026 Blood cells, normal values for, 497t Blood cultures in catheter-related infection, 995 in fever of unknown origin, 921 in infective arthritis, 985-986 in osteomyelitis, 987 samples for, 902-903 yield of, 930 Blood flow cerebral, 1124-1125, 1124f threshold for cell damage, 1125 regulation of coronary, 28-29, 98 pulmonary, 30 systemic, 29-30 renal, 290 Blood gases, arterial, in respiratory disorders, 195-197, 209, 209t acute respiratory failure, 259 chronic obstructive pulmonary disease, 217 Blood glucose monitoring, 703-704, 704t, 725 Blood pressure, arterial age-related changes in, 182-183, 183f estrogen replacement therapy and, 183-184 exercise and, 31 measurement of, 36, 174-175 ambulatory, 175, 176f, 185 myocardial oxygen consumption and, 28 oral contraceptives and, 183-184 regulation of, 29-30 Blood transfusion. See Transfusion. Blood urea nitrogen (BUN), 299, 299t in acute tubular necrosis, 363-364 serum osmolality and, 308 Blood volume gastrointestinal bleeding and, 386 regulation of, 30 Blue bloater, 216, 246 BNP. See Brain natriuretic peptide (BNP). BODE index, 217 Body dysmorphic disorder, 1081-1082 Body habitus, respiratory complaints and, 194, 197

Body mass index (BMI), 252 obesity and, 630, 632t, 633 Body temperature, regulation of, 910 Bone. See also Skeleton. peak mass of, 802 remodeling of, 773-775, 775f, 796f types of, 773-774, 774f Bone diseases, metabolic, 795-801. See also specific diseases. bone density measurements and, 795 definition of, 795 differential diagnosis of, 795-800, 795t future prospects for, 800b treatment of, 800 Bone loss, causes of, 802-804, 804t Bone marrow hematopoiesis in, 496-498 infiltrative diseases of, skeletal demineralization in, 795t, 800 Bone marrow biopsy in acute myeloid leukemia, 515 in aplastic anemia, 501 in hypoproliferative anemia, 522 in neutropenia, 537 Bone marrow failure. See Hematopoietic failure. Bone marrow fibrosis causes of, 510, 510t peripheral blood smear associated with, 535-536 Bone marrow transplantation. See also Stem cell transplantation. for aplastic anemia, 501-502 hepatic veno-occlusive disease secondary to, 486, 583 for multiple myeloma, 552 for renal cell carcinoma, 612 Bone mineral density, 802, 804-805, 805t, 806f, 807t vs. age, 802-804, 803f diagnostic significance of, 795, 800 osteoarthritis and, 870 Bone quality, 782b, 802, 803f in Paget disease, 811 Bone scan, in Paget disease of bone, 813-814, 815f Borchardt triad, 428-429 Bordetella pertussis infection, 193 Borrelia, 885, 917. See also Lyme disease. Bortezomib, 626t for multiple myeloma, 552 for Waldenström macroglobulinemia, 553 Bosentan, in systemic sclerosis for pulmonary hypertension, 848-849 for Raynaud phenomenon, 847, 848t Bosniak renal cyst classification, 337, 337t Botulinum toxin, 1193 in bioterrorism, 1045, 1048 for focal dystonia, 1114 for gastroparesis, 428 for headache, 1090, 1095b Botulism, 1193 Bounding pulse, 36-38 Boutonnière deformity, in rheumatoid arthritis, 824 Bovine spongiform encephalopathy, 884-885, 1163 Bowel sounds, 383 Bowman capsule, 286-288 BPN (benign prostatic hyperplasia), 752-756, 756t Brachial neuritis, acute autoimmune, 1174 Brachial plexopathy, 1174 Bradyarrhythmias, 122-123, 123f-124f after myocardial infarction, 114 pacemakers for, 140, 140t-141t Bradykinetic-rigid syndrome, drug-induced, 1113, 1113t Brain biopsy of, 1155 steroid administration and, 1157 circulation of, 1123-1125, 1124f coma with mass lesions of, 1058-1060, 1059f demyelinating disorders of. See Demyelinating disorders, central nervous system. herniation of, 1058 intracerebral hemorrhage with, 1132 lumbar puncture and, 1059 in stroke, 1131 tumor-associated, 1155-1156 uncal, 1155 hypoglycemia and, 722, 722t

1241

Brain (Continued) infection of. See Central nervous system infections. malformations of, 1120, 1120t Brain death, 1063, 1063t Brain injury, traumatic amnesia in, 1075-1076 epidemiology of, 1136 epilepsy secondary to, 1145 indications for surgery in, 1136 management of, 1136-1138, 1137t prognosis of, 1140 second impact syndrome in, 1136 Brain natriuretic peptide (BNP) in dilated cardiomyopathy, 151 in heart failure, 69-71 recombinant (nesiritide), in heart failure, 73 Brain tumors, 1154-1158 cause of, 1154 classification of, 1154 clinical manifestations of, 1154-1155 epidemiology of, 1154 evaluation of, 1155 future prospects for, 1158b headache caused by, 1091, 1091t, 1154-1155 lymphoma, primary CNS, 1022, 1023t, 1157 in HIV-infected patients, 1026 metastatic, 1154, 1157 specific tumors, 1156-1158 treatment of, 1155-1156 visual loss caused by, 1099 Brainstem abscess of, 1160 capillary telangiectases of, 1134 coma associated with mass lesions of, 1058, 1061 consciousness and, 1058 locked-in syndrome and, 1062, 1062t respiratory center in, 202-203 respiratory control disorders and, 246 stroke syndromes of, 1126 tumors of, diagnosis of, 1155 BRCA-1 and BRCA-2, 609-610 Breast cancer, 609-610 dose-dense chemotherapy for, 623, 627 endocrine therapy for, 626-627 evaluation of mass and, 746-747 gene expression signature in, 621-622 gene silencing in, 6 hypercalcemia in, 618-619, 786 male, 694 screening for, 600, 600t, 609-610 Breast development, staging of, 735, 736f Breast infection, 747 Breast mass, 746-747 Breast pain, 746-747 Breastfeeding amenorrhea secondary to, 740 anticoagulation during, 590 antiepileptic drugs and, 1152 Breath sounds, 194t, 195, 196t Breath tests, in malabsorption, 393-395 Breathing. See Respiratory physiology. Breathing frequency, 199 control of, 203 in mechanical ventilation, 261 Bretylium, 137t-138t, 139 Brief psychotic disorder, 1081 Broadbent sign, 38-39 Broca aphasia, 1068, 1070t Bromocriptine. See Dopamine agonists. Bronchi, 198, 199f Bronchial arteries, 30, 198-199 Bronchial veins, 30 Bronchiectasis, 190-191, 213, 214f, 214t, 220-221 high-resolution CT in, 210, 220 Bronchioalveolar lung cancer, 603 Bronchiolar disorders, 219-220. See also Bronchiolitis; Bronchiolitis obliterans. Bronchioles, 198, 199f Bronchiolitis, 219-220 acute viral, 219-220 in chronic obstructive pulmonary disease, 216 Bronchiolitis obliterans, 219-220 Bronchitis, hemoptysis in, 193

1242

Index

Bronchitis, chronic, 190-191, 213-214, 214f, 214t, 216. See also Chronic obstructive pulmonary disease (COPD). airway clearance techniques in, 219 definition of, 193, 216 epidemiology of, 189-190 respiratory control in, 246 Bronchoalveolar cell carcinoma, 267, 270 Bronchodilators in asthma, 223-224 in chronic obstructive pulmonary disease, 217-218 Bronchoprovocation testing, 209, 209f in asthma, 209, 209f, 223 Bronchopulmonary dysplasia, 189 Bronchoscopy, 197, 211 Bronchospasm algorithms for treatment of, 218f physical findings in, 196t as status asthmaticus, 224 Brown tumors, in hyperparathyroidism, 796, 797f Brown-Séquard syndrome, 1138-1139 Bruce treadmill protocol, 54-55 Brucellosis, 912t, 914 Brudzinski reflex, 1059, 1061f, 1091 Brugada syndrome, 143-144 Bruising. See Purpura. Bruits, 38 abdominal pain with, 383 Bubonic plague, 920 Budd-Chiari syndrome, 486 Budesonide, for Crohn disease, 436 Buerger disease, 169 Bulbospinal muscular atrophy, 1173-1174 Bulimia nervosa, 635-637, 636t Bullectomy, for emphysema, 219 BUN. See Blood urea nitrogen (BUN). Bundle branch block electrocardiography in, 50-51, 50t, 51f in myocardial infarction, 114 rate-related, 51 Bundle branches, 24, 24f Buprenorphine, for opioid abuse, 1229 Burkitt lymphoma, 545-546 in HIV-infected patient, 553 Bursae, classification of, 873 Bursitis, 873-875, 874t septic, 874-875, 987 Butterfly glioma, 1155 Bypass tracts. See Accessory pathways. C CA-125, ovarian cancer and, 613 Cabergoline, valvular regurgitation caused by, 60, 61f. See also Dopamine agonists. CABG. See Coronary artery bypass grafting (CABG). Cachexia in HIV-infected patients, 1025 in malignancy, 194-195 in obstructive lung disease, 219 CAD. See Coronary artery disease (CAD). CAGE questionnaire, 1223, 1223t Calcidiol, 776-777 Calcimimetics, 374 Calciphylaxis, in chronic kidney disease, 375 Calcitonin, 671, 777 for hypercalcemia, 618, 618t measurements of, 671 for osteoporosis, 808t, 809 for Paget disease of bone, 815-816, 815t Calcitriol, 773, 776-777. See also Vitamin D. Calcium, 772-778. See also Hypercalcemia; Hypocalcemia. fractional absorption of, 773 gastrointestinal secretion of, 773, 782b homeostasis of extracellular fluid and, 772-775, 773f integration of, 777-778, 777f-778f regulatory hormones and, 775-777, 776f intestinal absorption of, 773, 773f, 776-777 myocardial contraction and, 25, 26f physiologic roles of, 772 renal handling of, 293-294, 773, 773f

Calcium (Continued) serum, 772 parathyroid hormone and, 775-776 skeletal fluxes of, 773-775, 773f parathyroid hormone and, 776 supplementation of in hypoparathyroidism, 789 for osteoporosis prevention, 805 in Paget disease of bone, 815-816 Calcium channel, neuromuscular junction, LambertEaton syndrome and, 1192-1193 Calcium channel blockers for angina pectoris, 103t, 104 variant, 106 for arrhythmias, 138, 138t contraindications to, 181t-182t in heart failure, 72 for hypertension, 179-180, 179t-180t, 182-183 for hypertensive emergency, 185, 185t in hypertrophic cardiomyopathy, 152 for kidney stone passage, 341 after myocardial infarction, ST-segment elevation, 111 for non–ST-segment elevation myocardial infarction, 108-109 perioperative, with noncardiac surgery, 279 for pulmonary hypertension, 170, 243-244 for Raynaud phenomenon, 169, 847 side effects of, 181t-182t for unstable angina, 108-109 Calcium channelopathies, 1186t, 1188 Calcium pyrophosphate deposition disease (pseudogout), 780, 867f hemochromatosis associated with, 880 in hyperparathyroidism, 882 in hypothyroidism, 882 Calcium pyrophosphate dihydrate, in osteoarthritis, 871 Calcium stones, urinary, 342-344, 342t Calcium-sensing receptor (CaSR), renal, 292-293, 293f mutations affecting, 315, 321 Caloric requirements, 639 Caloric restriction, lifespan and, 1198 Caloric testing, 1061-1062, 1062t-1063t Campylobacter jejuni infection, 980-981, 981t, 984 Guillain-Barré syndrome associated with, 1179 in HIV-infected patients, 1024, 1025t Cancer. See also Tumor(s); specific cancers. complications in, 616-620. See also Hypercalcemia, cancer-associated; Paraneoplastic syndromes. febrile neutropenia, 616-617 long-term, 619t, 620 spinal cord compression, 617 superior vena cava syndrome, 267, 617-618 thrombosis, 585, 616 diagnosis of, 621 epidemiology of, 598, 599t epigenetics of, 596 fever associated with, 910-911, 921-922 future prospects for, 597b, 601b, 615b genetics of, 11, 594-596, 595t, 596f hereditary syndromes of, 601, 601t metastatic, 594, 609 diffuse meningeal involvement in, 939 staging of, 621 molecular signature of resected tissue, 1158b myositis associated with, 850-852 phenotype characteristic of, 594, 595t prevention of, 598-601 chemopreventive agents for, 600, 600t genetic testing and, 601, 601t risk factors and, 598-600, 599t screening of women for, 734t screening tests for, 600-601, 600t rheumatic syndromes associated with, 878, 879t staging of, 621-622 systemic lupus erythematosus and, 839 treatment of, 621-628. See also Chemotherapy; Radiation therapy; Stem cell transplantation. biologic agents in, 627 diagnosis and staging for, 621-622 endocrine therapy in, 626-627 future prospects for, 621, 627b palliative, 622, 624, 627 supportive interventions in, 627

Cancer (Continued) surgery in, 622 targeted therapy in, 625-626, 626f, 626t Cancer stem cells, 596-597, 615b, 1158b Candida infection, 888 catheter-associated of bladder, 993 of bloodstream, 995 dermatitis in, in HIV-infected patients, 1020t disseminated, skin lesions in, 969, 1031-1032 esophageal, 413 in HIV-infected patients, 1019, 1021, 1021t hepatic abscesses in, 975-976 hepatosplenic, 1031-1032 oral, 946 in HIV-infected patients, 1020 osteoarthritis in, 986-987 vulvovaginal, 1005, 1005t in HIV-infected patients, 1014-1015, 1021 Candidate gene approach, 10-11 Cannabinoids, 1225t-1228t, 1231, 1233b. See also Endocannabinoids. Cannon a waves, 36, 37f Capacitance vessels, 30 Capillaritis, pulmonary, 236-237 Capillary telangiectases, brainstem, 1134 Caplan syndrome, 825-826 Capsaicin, topical, for osteoarthritis pain, 872 Capsule endoscopy. See Video capsule endoscopy. Captopril for cystine stones, 344 in hypertensive urgency, 185 Captopril renography, 347 Capture beats, 130, 132 Carbamazepine, 1149-1150, 1150t neural tube defects and, 1151-1152 toxicity in Asian patients, 1149-1150 Carbidopa, 1112, 1112t Carbohydrate counting, 705, 707 Carbohydrates digestion and absorption of, 389 malabsorption of, 393-394, 398 Carbon dioxide acid-base balance and, 316-317 ventilatory response to, 202-203, 203f Carbon dioxide–hemoglobin dissociation curve, 204, 205f Carbon monoxide, binding by hemoglobin, 204 Carbon monoxide poisoning, 264-265, 264t parkinsonism secondary to, 1114 Carbonic acid, in blood, 204 Carbonic anhydrase of proximal tubule, 292, 316-317 mutations in, 319 in red blood cells, 204 Carbonic anhydrase inhibitors, 307-308, 308t Carbuncles, 969, 970t Carcinoid syndrome, 443 Carcinoid tumors, gastrointestinal, 443-444 Cardiac arrest. See also Sudden cardiac death. coma after, prognosis in, 1061-1062, 1062t Cardiac catheterization, 58-60. See also Coronary angiography. in angina pectoris, 102 with atrial septal defect, 76-77 in hypertrophic cardiomyopathy, 152 in mitral regurgitation, 90 in mitral stenosis, 89 before noncardiac surgery, 277, 278f in restrictive cardiomyopathy, 154t right ventricular, 60, 61f in pulmonary arterial hypertension, 170 right-sided in cardiac tamponade, 147 in constrictive pericarditis, 147-148, 148f in pulmonary hypertension, idiopathic, 243 with ventricular septal defect, 77 Cardiac cycle, 26-30, 27f Cardiac fibrosis, in systemic sclerosis, 846, 846t Cardiac impulse, 118 Cardiac index, 27, 59-60 in shock, 263t Cardiac output, 27 exercise and, 30-31 measurement of, 59-60, 62t

Index Cardiac output (Continued) regulation of, 30 sex differences in, 732-733 Cardiac performance factors affecting, 27-28, 28t measures of, 27-28, 28t Cardiac surgery, 158-161. See also Cardiac transplantation; Coronary artery bypass grafting (CABG). cytomegalovirus postperfusion syndrome following, 923 Cardiac transplantation, 73-74, 160 Cardiac tumors, 156, 157t CARDIO 2000 Study, 16-17 Cardioembolism, stroke caused by, 1125, 1125t, 1128-1130 Cardiogenic shock, 262, 263t in acute aortic regurgitation, 87 in acute mitral regurgitation, 90 in myocardial infarction, 110-112, 114-115 Cardiomyopathy(ies), 149, 150t. See also Heart failure. amlodipine in, 72 arrhythmogenic right ventricular, 149, 150t, 154-155 causes of, 66, 67t classification of, 149 definition of, 66 digoxin in, 72-73 dilated. See Dilated cardiomyopathy. external containment devices for, 74b hypertrophic. See Hypertrophic cardiomyopathy. magnetic resonance imaging in, 60-61, 62f myocarditis resulting in, 148-149 peripartum, 151, 164 restrictive. See Restrictive cardiomyopathies. tachycardia-induced, 151 unclassified, 150t, 155 Cardiopulmonary bypass aprotinin in, 580-581 dilutional thrombocytopenia secondary to, 571-572 Cardiopulmonary exercise testing, preoperative, in lung cancer, 270-271 Cardiovascular disease. See also Coronary artery disease (CAD). antihypertensive therapy and, 186 chronic kidney disease with, 369, 373, 373f dialysis and, 376 diabetes and, 97, 116-117, 701, 718-719 evaluation of, 32-65. See also specific tests. auscultation in, 39-45. See also Murmurs. cardiac catheterization in, 58-60 chest radiography in, 46, 47f computed tomography in, 62-64, 64f echocardiography in, 40-42, 56f-58f electrocardiography in, 46-49 functional status in, 35-36, 35t history in, 32-35 magnetic resonance imaging in, 60-61, 62f-63f peripheral vascular disease in, 38, 64-65 physical examination in, 36-39 pulmonary artery catheterization in, 60, 61f radionuclide imaging in, 55-58, 59f stress testing in, 53-55 future prospects for, 164b noncardiac surgery and. See Surgery, noncardiac, cardiovascular disease and. in pregnant patient. See Pregnancy, with cardiovascular disease. systemic lupus erythematosus and, 839 in women, 731-732, 745-746 diabetes and, 746 estrogen and, 743 menopause and, 744-745 Cardioversion, direct current, 141 for atrial fibrillation, 126-127 for ventricular fibrillation, 131 for ventricular tachycardia, 130-131 Caregivers, of older adults, 1205 Caretaker (stability) genes, 595t, 596 Carotene β carotene for erythropoietic porphyria, 657 lung cancer and, 268 serum, steatorrhea and, 393-394

Carotid artery atherosclerosis of, visual loss caused by, 1099 cerebral blood supply from, 1123, 1124f internal, stroke associated with, 1126-1128, 1127t prevention of, 1130 Carotid artery pulse, 36-38, 38f Carotid body, 202-203 Carotid endarterectomy, 1130 Carotid shudder, 36-38 Carotid sinus massage, 131-132, 132f, 134 Carpal spasm, 772, 788 Carpal tunnel syndrome, 1175t, 1178-1179 in diabetes mellitus, 881 in rheumatoid arthritis, 824 Carvedilol in heart failure, 73 for hypertension, in diabetic patient, 182 Case reports, 16-17 Case series, 16-17 CaSR. See Calcium-sensing receptor (CaSR), renal. Casts, urinary, 300-301, 301t Catamenial epilepsy, 1141 Catamenial pneumothorax, 250 Cataplexy, narcolepsy with, 1066 Cataracts, in diabetic patients, 717-718 Catatonic stupor, 1062 Catecholamines, glucose counter-regulation and, 700, 721-722 Catheter ablation, radiofrequency, 142 for atrial fibrillation, 126-127, 127f, 142 for atrioventricular nodal re-entrant tachycardia, 128, 142 for automatic junctional tachycardia, 128-129 for ventricular tachycardia, 130-131, 142 Catheter-associated infections bloodstream, 995, 997t, 1033 urinary tract, 993, 993t Catheters, for vascular access, 995, 996t Cat-scratch disease, 919-920 Cauda equina syndrome, 1095 Cavernous angioma, 1134 Cavernous sinus thrombosis, septic, 1162. See also Cerebral venous sinus thrombosis. CCR5 chemokine receptor, 1010-1012 CD4 T cells, 539-540, 892-893, 895-896 in HIV infection, 1010-1015, 1012f disease progression and, 1017f increasing viral load and, 1019 initiation of treatment and, 1016t, 1017 monitoring interval for, 1016 opportunistic infections and, 1014, 1015t, 1019-1020 Celiac disease, 394-395 hypophosphatemia in, 792 Cell-mediated immune deficiency agents causing infection in, 1028-1029, 1029t in AIDS, 1009 causes of, 1028-1029, 1029t Cellulitis, 972-974, 972t clostridial, 973 vs. deeper infection, 974 mimics of, 972, 972t, 974 Centimorgans (cM), 9 Central nervous system infections, 933-944, 1159-1164. See also Encephalitis; Meningitis; Meningoencephalitis. brain abscess, 1159-1160, 1160f infective endocarditis with, 962, 1162-1163 parasitic, 942, 943f subdural empyema leading to, 1160 clinical presentation of, 933 diagnostic evaluation in, 933-934, 934t. See also Cerebrospinal fluid (CSF). fungal, 942-944 future prospects for, 944b in HIV-infected patients, 1021-1023, 1022t-1023t immune response modifiers associated with, 942-944, 943t infective endocarditis complicated by, 962, 1162-1163 in malignant external otitis, 1161 parasitic, 942, 942f-943f prion diseases, 884-885, 1075, 1163-1164, 1163f spinal epidural abscess, 1161-1162, 1161f subdural empyema, 1160-1161

1243

Central nervous system infections (Continued) tuberculous, 938-939, 941-942 in HIV-infected patients, 1023 spinal epidural abscess, 1162 of venous sinuses, 1162 Central nervous system tumors. See Brain tumors; Spinal cord tumors. Central sympatholytic agents, 179t-182t Central venous catheters, infections related to, 995, 996t, 1033 Cerebellar ataxias, 1116-1117, 1117t Cerebellar system impairment, signs of, 1109, 1111t Cerebellar tremor, 1114 Cerebellum acute infarction of, 1127 cortical zones of, 1116 hemorrhage in, 1132-1133, 1133t medulloblastoma of, 1157 motor cortex and, 1108-1109, 1109f-1110f, 1116 paraneoplastic degeneration of, 619t Cerebral blood flow, 1124-1125, 1124f threshold for cell damage, 1125 Cerebral edema, 1125 brain tumor causing, 1156-1157 in fulminant hepatic failure, 476, 477t, 483 hypernatremia correction and, 312 in hypertensive encephalopathy, 1131 hyponatremia with, 311 intracerebral hemorrhage with, 1132 magnetic resonance imaging of, 1147-1148, 1159, 1160f management of, 1131 after traumatic brain injury, 1138 Cerebral hypoxia, 1125 Cerebral infarction, 1125 imaging of, 1128, 1129f lacunar, 1126 Cerebral ischemia. See also Stroke, ischemic. causes of, 1125, 1125t perfusion pressure and, 1124-1125 Cerebral perfusion pressure, 1124-1125 in traumatic brain injury, 1137-1138 Cerebral venous sinus thrombosis, 1099, 1128, 1128t diagnostic evaluation in, 1128 septic, 1162 subdural empyema leading to, 1160-1161 treatment of, 1131-1132 Cerebral venous sinuses anatomy of, 1124 idiopathic intracranial hypertension and, 1103b malformations of, 1134 Cerebritis, 1159-1160 Cerebrospinal fluid (CSF). See also Lumbar puncture. brain tumor and, 1155 in comatose patient, 1059 Creutzfeldt-Jakob disease and, 1075, 1163-1164 in demyelinating neuropathy, 1178 diagnosis of infection in, 933, 934t with India ink preparation, 898, 899f, 938-939 with microbial antigens, 898-899, 899t with molecular diagnostics, 900-901 in encephalitis, 940 hypocretin in, in narcolepsy, 1066 immunoglobulin G in in multiple sclerosis, 1166, 1167t in transverse myelitis, 1169-1170 in infective endocarditis, 1162-1163 laboratory analysis of, 1054-1055 in meningitis acute bacterial, 933, 934t, 935-936 aseptic, 937 subacute or chronic, 938-939 in multiple sclerosis, 1165-1166, 1168f vs. neuromyelitis optica, 1169 rhinorrhea of, 945-946 seizures and, 1148 subarachnoid hemorrhage and, 1134 in syphilis, 1001-1002 Cerebrovascular disease, 1123. See also Aneurysm(s), intracranial; Stroke. anatomic basis of, 1123-1124, 1124f physiologic basis of, 1124-1125, 1124f surgical risk and, 274-276, 275t vascular malformations, 1134-1135 Certolizumab pegol, for Crohn disease, 437

1244

Index

Ceruloplasmin, 651-652, 652t Cervical cancer, 613-614 human papillomavirus and, 599, 613, 741, 1006 screening for, 600, 600t, 613 Cervical dysplasia, in HIV-infected women, 1014-1015, 1021 Cervical mucus, 732f, 733 Cervical radiculopathy, 1093-1094, 1094t Cervical spine headache associated with, 1086 spondylosis of, 1093-1094, 1094f subluxation of, in rheumatoid arthritis, 824 Cervicitis gonococcal, 1003-1004 nongonococcal, 1004-1005 Cetuximab, 625, 626t CHADS score, 1128-1130 Chagas disease, 1038 dilated cardiomyopathy in, 148 Chancroid, 920, 999t in HIV-infected patients, 1021 Channelopathies, 1186t, 1187-1188 cardiomyopathies associated with, 150t epilepsy in, 1142 Charcot joints, 881 Charcot triad, 492-493 Charcot-Bouchard aneurysms, 1132 Charcot-Marie-Tooth disease, 1180-1181 Chédiak-Higashi syndrome, 572t, 573, 1030 Cheiroarthropathy, diabetic, 881 Chemical weapons, 1044, 1045t-1046t, 1048-1049 Chemicals. See Toxins. Chemokine receptor CCR5, 1010-1012 Chemokines, 892-893 Chemopreventive agents, cancer and, 600, 600t Chemotaxis, of neutrophils, 533, 1030 Chemotherapy, 622-627, 623t-624t for brain tumors, 1156 metastatic, 1157 long-term effects of, 619t, 620 neutropenia-associated infections and, 1030-1031 pulmonary toxicity of, 234, 235t support for side effects of, 627 Chenodeoxycholic acid, for gallstones, 491 Chest, physical examination of, 194-195, 194t Chest pain, 32-33, 33t-34t in acute coronary syndrome, 106 in esophageal disease, 409 in lung cancer, 267 in pericarditis, 145-146 in respiratory disease, 193 Chest radiography in acute respiratory distress syndrome, 262 with atrial septal defect, 76t with bronchiectasis, tram tracks in, 220 in cardiovascular disease, 46, 47f in chronic obstructive pulmonary disease, 217 in heart failure, 70, 70f in interstitial lung diseases, 226, 227f asbestosis, 237-238 coal worker’s pneumoconiosis, 237 in connective tissue disorders, 233 eosinophilic pneumonia, chronic, 239 idiopathic pulmonary fibrosis, 227f, 230 sarcoidosis, 232, 232t silicosis, 237 for lung cancer screening, 268 of pleural effusion, 210, 248 in pneumonia, 254-255, 953, 953t Pneumocystis jiroveci, 257, 953 tuberculous, 957 of pneumothorax, 250 in pulmonary embolism, 172, 242 in pulmonary hypertension, idiopathic, 243 in respiratory disorders, 197, 210 in tuberculosis, disseminated, 922 in valvular heart disease, acquired, 86t Chest wall, 251 Chest wall disease, 251-253 Cheyne-Stokes respiration, 246-247 Chiari malformation, 1119-1120 Chickenpox, 917, 970-971 vs. smallpox, 1047

Chills, 911 in sepsis syndrome, 928-929 Chinese herb nephropathy, 335 Chinese liver fluke, 1040 Chlamydia psittaci infection, 885 Chlamydia trachomatis infection, 885 in adolescent and young women, 735 cervicitis in, 1004-1005 with gonococcal co-infection, 1003 laboratory diagnosis of, 902t reactive arthritis secondary to, 829-833 screening of women for, 734t urethritis in, 1004-1005 urinary tract, 989-991 Chlamydiae, 885 laboratory detection of, 902 Chlamydophila pneumoniae infection, 885, 956-957, 959t Chloramphenicol, mechanism of action, 4 Chloride fluid compartments and, 305, 306f intestinal transport of, 396-397, 397f renal transport and, 292-296 urinary, metabolic alkalosis and, 321 Chloride channelopathies, 1186t, 1187 Chloroquine for malaria, 1037 for malaria prophylaxis, 1035-1036 for porphyria cutanea tarda, 656-657 for systemic lupus erythematosus, 838 Chlorpropamide, 708-709, 710t-713t Cholangiocarcinoma, 493-494, 494f inflammatory bowel disease with, 434 primary sclerosing cholangitis with, 493-494, 494b Cholangiography, in jaundice evaluation, 464, 464f Cholangitis acute, 490-493, 490f biliary parasites and, 493 primary. See Primary sclerosing cholangitis. Cholecystectomy for acalculous cholecystitis, 492 after acute cholangitis treatment, 493 for acute cholecystitis, 492, 492f for biliary colic, 491 for gallbladder polyps, 494 laparoscopic, 491 after pancreatitis attack, 493 prophylactic, 491 Cholecystitis acalculous, 492 acute, 490-492, 492f chronic, 490-491 radionuclide studies in, 407, 492 Cholecystokinin, 488 satiety and, 631 Choledocholithiasis (common bile duct stones), 490f, 491-493, 492f Choledochoscopy, 403 Cholelithiasis. See Gallstones. Cholera. See Vibrio cholerae infection. Cholescintigraphy, 407, 492 Cholestasis hyperbilirubinemia in, 463-464 tests of, 456-458, 457t Cholestatic hepatitis, viral, 469 Cholesterol, 643. See also High-density lipoprotein (HDL) cholesterol; Lipoproteins; Low-density lipoprotein (LDL) cholesterol. in bile, 488-490 coronary artery disease and, 97 dyslipidemia and, 644-650 fecal excretion of, 488 metabolism of, 643-644, 644f-645f in pleural fluid, 249 Cholesterol absorption inhibitors, 647, 647t Cholesterol emboli, 331, 351 Cholesterol gallstones, 488-490 oral therapy for, 491 Cholestyramine, for bile salt malabsorption, 437 Cholinesterase inhibitors. See Acetylcholinesterase inhibitors. Chondrocalcinosis, 821, 869 in hemochromatosis, 880 in hyperparathyroidism, 882 Chondroitin sulfate, for osteoarthritis pain, 872

Chordae tendineae, anatomy of, 22 Chorea, 1109, 1111t, 1115 Choreoathetosis, 1111t Choriomeningitis, lymphocytic, 937 Chromatin gene regulation and, 4-6, 6f structure of, 5-6, 6f Chromosomal mutations, 7, 7t genetic diseases caused by, 11-12 identification of, 11 Chromosome(s), number of genes in, 2 Chronic granulomatous disease, 533, 1030 Chronic inflammatory demyelinating polyneuropathy, 1180 Chronic kidney disease (CKD), 369-379. See also End-stage renal disease (ESRD); Renal failure, chronic; Renal insufficiency. acquired cystic kidney disease secondary to, 339 vs. acute kidney injury, 362, 363t, 369 classification of, 369, 370t clinical manifestations of, 372-375, 373f-374f factors causing, 372, 372f definition of, 369 diabetes mellitus with, 370-371, 370t insulin requirement and, 374 future prospects for, 379b hypertension and, 182, 184, 350, 370 immune dysfunction in, 374 interstitial nephritis progressing to, 334 management of, 370-375 acute deterioration and, 372, 372f, 372t in diabetic patients, 370-372 diet in, 371, 371t drug toxicities and, 371-372, 372t goals of, 370 hypertension in, 370-372 preventing progression in, 370 pathophysiology of, 369-370, 371f prevalence of, 369, 370t screening for, 370-371 vascular disorders and, 345 Chronic obstructive pulmonary disease (COPD), 213-215, 214t. See also Bronchitis, chronic; Emphysema; Small airways disease. acute exacerbations of, 214-215, 218-219, 218f antibiotic therapy in, 219 classification of, 213, 214f clinical manifestations of, 216 end-of-life issues in, 219 epidemiology of, 189-190, 214 evaluation of, 216-217 local immune response in, 216 management of, 217-219, 218f prognosis of, 217 Chronic pelvic pain syndrome, 758 Churg-Strauss syndrome, 225, 236-237, 327, 859f, 860 Chvostek sign, 788 Chylomicronemia syndrome, 645-646, 649-650 Chylomicrons, 643-645, 644f, 644t Ciliary dyskinesia, bronchiectasis in, 220 Cilostazol, in peripheral arterial disease, 166 Cimetidine, for peptic ulcer disease, 423 Cinacalet, for hyperparathyroidism, 796-800 Ciprofloxacin, in inflammatory bowel disease, 436 Circadian rhythm sleep disorders, 1066 Circinate balanitis, 831 Circle of Willis, 1124 Circulation, systemic, physiology of, 29-30 Circulatory pathway, 22-24, 23f Circumcision, HIV transmission and, 1026 Cirrhosis, 478-487 alcoholic, 471, 478 causes of, 478, 479t chronic viral hepatitis and, 473-474, 478 clinical features of, 478, 479t complications of, 479-480, 480f ascites as, 479, 480f, 481-482, 482f, 482t hepatic encephalopathy as, 479, 483-484, 484t hepatocellular carcinoma as, 479, 484-485, 485t hepatocellular dysfunction and, 478-479 hepatopulmonary syndrome as, 479, 484-485 hepatorenal syndrome as, 479, 483 portal hypertension and, 478-480 spontaneous bacterial peritonitis as, 479, 482-483 variceal hemorrhage as. See Variceal hemorrhage.

Index Cirrhosis (Continued) diagnosis of, 478-479 future prospects for, 487b inflammatory bowel disease with, 434-435 liver function tests in, 458 in nonalcoholic steatohepatitis, 474 pathogenesis of, 478, 479t pleural effusion in, 249 primary biliary, 463-464, 881 cis-acting regulatory elements, 5 disease phenotype and, 12 Cisapride, 428 Cisplatin, 623t nephrotoxicity of, 366 Citrate. See Hypocitraturia. CK. See Creatine kinase (CK). CKD. See Chronic kidney disease (CKD). CK-MB. See Creatine kinase muscle band (CK-MB). Claude syndrome, 1126 Claudication, 38, 64-65, 165-167 in Buerger disease, 169 jaw, 169 in Takayasu arteritis, 169 Clear cell carcinoma of kidney, 612 of lung, 267 Clicks, systolic, 41, 42f Clinical practice guidelines, 17 Clinical pulmonary infection score (CPIS), 994 Clinical trials. See Research studies. Clonic movements, 1143 Clonidine in hypertensive urgency, 185 for opioid withdrawal, 1229 Clonidine suppression test, 689-690 Clonorchis sinensis infection, 1040, 1040t Clopidogrel after acute coronary syndrome, 116-117 in coronary artery disease, 102-103 mechanism of action, 581-582 in myocardial infarction non–ST-segment elevation, 109 ST-segment elevation, 110-113 perioperative, with noncardiac surgery, 279 in peripheral arterial disease, 166 after stent implantation, 104-105 for stroke prevention, 1132 for unstable angina, 109 Clostridium botulinum. See Botulinum toxin. Clostridium difficile colitis, 980, 981t, 982, 984, 995 with fever, 923 in HIV-infected patients, 1024, 1025t Clostridium perfringens infection, diarrhea in, 980 Clostridium species, 886 cellulitis caused by, 973 myonecrosis caused by, 974 Closure time, 556-557, 564 Clubbing in hypertrophic osteoarthropathy, 878 in respiratory diseases, 194-195 in thyroid acropachy, 882 Cluster headache, 1088-1090, 1095b cM (centimorgans), 9 CMV. See Cytomegalovirus (CMV) infection. Coagulation, 560-562. See also Hemostasis. cascade model of, 557f, 560-562 laboratory testing of, 561-562 Coagulation factors bleeding disorders associated with, 565f, 576-577, 576t transfusion of, 578-579, 578t Coagulopathy dilutional, 573-574, 577 in fulminant hepatic failure, 476-477, 477t in sepsis, 927-929 Coal worker’s pneumoconiosis, 228t-229t, 237 Coarctation of aorta, 78t, 79-80, 80f hypertension secondary to, 177t noncardiac surgery in patient with, 282 Cobalamin. See Vitamin B12 (cobalamin). Cobb angle, 251-252, 252f Cocaine, 1225t-1228t, 1230-1231 “crack lung” secondary to, 234 heat stroke caused by, 1084 heroin with, 1229-1230

Cocaine (Continued) myocardial ischemia or infarction caused by, 97-98, 1230, 1231f pulmonary toxicity of, 234, 235t Coccidioides immitis infection, 888 disseminated, in HIV-infected patients, 1024 meningitis in, 938, 942, 1023 Cockroft-Gault formula, 299, 299t Codeine, 1214t Co-dominant circulation, 23-24 Codons, 3f, 4 Cognitive behavioral therapy for alcoholism, 1223 for anxiety disorders, 1081 for insomnia, 1064 for weight loss, 632t, 633 Cognitive disorders, 1077, 1078t Cohort studies, 16-17 of women, 731 Colchicine in calcium pyrophosphate deposition disease, 869 for gout, 867-868, 867t-868t Cold agglutinin disease, 528 Waldenström macroglobulinemia with, 552-553 Cold immune hemolysis, 527-528 Colitis. See Clostridium difficile colitis; Hemolytic uremic syndrome, hemorrhagic colitis in; Ulcerative colitis. Collagen in Alport syndrome, 330 bleeding disorders and, 565-566 of glomerular basement membrane, 289 platelet binding to, 558-559 Collagen vascular diseases. See also Connective tissue diseases. fever in, 922 interstitial lung disease in, 228t-229t Collecting ducts, renal functions of, 293-294, 294f-295f potassium secretion, 294-296 water reabsorption, 296 structure of, 286-290, 287f Colography, computed tomographic, 406, 442-443 Colon biopsy in Crohn disease, 433, 434f in ulcerative colitis, 433, 434f Colonoscopy, 402 for bleeding, 388 colorectal cancer and for diagnosis, 442 for screening, 442-443, 443t, 608 in Crohn disease, 433, 433f in ulcerative colitis, 432-433, 433f virtual, 406, 442-443 Colorectal cancer, 441-443, 607t, 608-609 clinical presentation of, 442, 608 in Crohn disease, 432 diagnosis of, 442-443, 608 epidemiology of, 441-442, 608 genetics of, 596, 596f, 608 hereditary nonpolyposis, 441-442, 596, 608 molecular tumorigenesis in, 441, 442f natural history of, 608 prevention of, 608 risk factors for, 441, 442t screening and surveillance for, 442-443, 443t, 600, 600t staging of, 608t survival by stage of, 443, 443t treatment of, 443, 608-609 monoclonal antibodies in, 625-626, 626t ulcerative colitis and, 432, 436 Coma, 1058-1063 definition of, 1058 diagnostic approach to, 1058-1061 history in, 1058-1059 motor response in, 1059-1060, 1059f pupillary reactivity in, 1059f, 1060-1061 reflex eye movements in, 1058, 1059f, 1061 signs of meningitis in, 1059, 1061f structural vs. metabolic causes and, 1059-1061, 1059f differential diagnosis of, 1058, 1060t emergency management in, 1059, 1060t thiamine with glucose in, 1076

1245

Coma (Continued) functional imaging in, 1063b pathophysiology of, 1058, 1059f, 1059t pharmacologic, in traumatic brain injury, 1137 prognosis in, after cardiac arrest, 1061-1062, 1062t Coma-like states, 1062-1063, 1062t brain death as, 1063, 1063t Common bile duct stones (choledocholithiasis), 490f, 491-493 Common cold, 948 Complement deficiency glomerular diseases with, 325, 325t neutrophil dysfunction and, 1030 Complement system, 891-892, 891f, 894-895 in antibody-dependent defense, 896 in antiviral defense, 897 Complete heart block, 123, 124f jugular venous pulse in, 36, 37f Complex partial seizures, 1143-1144, 1143t Complex regional pain syndrome, 1093 Computed tomographic angiography (CTA) of aortic aneurysm, 167-168, 167f of aortic dissection, 168, 168f of aortic trauma, 157-158 of aortic ulcer, penetrating, 168, 169f of coronary arteries, 63-64, 64f, 102 in peripheral arterial disease, 65, 166 in pulmonary embolism, 172-173, 172f, 210, 243 of pulmonary vascular system, 210 of renal artery stenosis, 177, 178f, 347 Computed tomographic colonography, 406, 442-443 Computed tomographic enterography, 406 in Crohn disease, 433 Computed tomographic venography, of renal vein thrombosis, 356-357 Computed tomography (CT) in abdominal pain, 384 cardiac, 62-64, 64f gated, of prosthetic valves, 93, 93f in coma, 1058-1059, 1060t electron-beam, of coronary calcification, 97, 102 in emphysema, 217 in epilepsy, 1148 of gastrointestinal tract, 406 high-resolution in bronchiectasis, 210, 220 in bronchiolar disorders, 220 in desquamative interstitial pneumonia, 231 in idiopathic pulmonary fibrosis, 230, 230f in interstitial lung disease, 225-226 in nonspecific interstitial pneumonia, 231 in pulmonary disorders, 210, 217 in sarcoidosis, 232 in hypersensitivity pneumonitis, 238 of kidney, 303 of lung cancer for evaluation, 268 for screening, 268 vs. magnetic resonance imaging, 1056t multidetector of chest, 210 of coronary calcification, 97, 102 of pulmonary embolism, 172-173, 172f in nephrolithiasis, 341 in neurologic disease, 1056, 1056t in pancreatitis acute, 448-450, 450f chronic, 451, 452f PET integrated with, 211 of pleural effusion, 248 in pulmonary alveolar proteinosis, 240 in pulmonary disorders, 197, 210 in pulmonary embolism, 172-173, 172f, 242-243, 242f quantitative, of bone mass, 804-805, 807t of renal cell carcinoma, 612 of renal cysts, 337 of solitary pulmonary nodule, 270 in stroke, 1128, 1129f hemorrhagic, 1132-1133 of subarachnoid hemorrhage, 1134 Concussion amnesia associated with, 1070-1071 grading of, 1136, 1137t postconcussive syndrome, 1138

1246

Index

Conduction abnormalities after myocardial infarction, 114 noncardiac surgery in patient with, 162 Conduction aphasia, 1068-1070, 1070t Conduction system, cardiac, 24, 24f blood supply to, 24 cells of, 25 ischemic injury to, 98 normal impulse of, 118 Condyloma acuminatum, 999t Confusion, 1058-1059, 1202 Congenital adrenal hyperplasia, 683-684 Congenital heart disease, 75-83 aortic coarctation, 78t, 79-80, 80f hypertension secondary to, 177t noncardiac surgery in patient with, 282 atrial septal defects, 75-77, 76f, 76t Ebstein anomaly with, 79 clinical presentations of, 75 coronary artery anomalies, 82-83 myocardial ischemia caused by, 97-98 Eisenmenger syndrome in, 76-77, 80, 82 epidemiology of, 75 future prospects for, 83b infective endocarditis associated with, 961 noncardiac surgery in patient with, 282 patent ductus arteriosus, 76f, 76t, 80 pregnancy in patient with, 163 single ventricle, 82 tetralogy of Fallot, 78t, 81 noncardiac surgery in patient with, 282 pregnancy in patient with, 163 transposition of great arteries, 81-82 valvular, 77-79 aortic valve, 77-79, 78t, 84-85 pulmonic valve, 78t, 79 tricuspid valve, 78t, 79 ventricular septal defects, 75-77, 76f, 76t in tetralogy of Fallot, 81 Congestive heart failure. See Heart failure; Pulmonary edema. Congophilic amyloid angiopathy, 1132-1133 Conivaptan for hyponatremia, 310-311 refractory ascites and, 482 Conjugate vaccines, 895-896 Conjunctivitis with preauricular lymphadenopathy, 920 in spondyloarthropathies, 829, 831 Connective tissue diseases. See also Collagen vascular diseases; Rheumatic diseases. fever of unknown origin and, 921 interstitial lung diseases in, 225-226, 231, 233-234, 234t mixed, 836-837, 847 oral ulcerations in, 947 pulmonary capillaritis in, 236 undifferentiated, 836-837 Connective tissue screen, 818 Consciousness anatomic substrate of, 1058 disorders of. See Coma. seizures and, 1143 Consolidation, pulmonary, physical findings in, 196t Constipation, in irritable bowel syndrome, 384-385 Constitutively expressed genes, 5 Constrictive pericarditis, 147-148, 148f anasarca with ascites in, 35 effusive, 148 jugular venous pulse and, 36, 37f vs. restrictive cardiomyopathies, 154, 154t Continuous positive airway pressure (CPAP) for sleep-disordered breathing, 246, 252, 253b in weaning from mechanical ventilation, 261-262 Contraception, 737-738, 737t. See also Oral contraceptives. emergency, 738 perimenopausal, 742 systemic lupus erythematosus and, 839 Contractility, cardiac, 27-28, 28t. See also Inotropic agents. exercise and, 30-31 myocardial oxygen consumption and, 28 Contractures, muscle, 1182-1183

Contrast media–associated nephropathy, 365-366, 365t, 371-372 Conversion disorder, 1081-1082 Convulsions, 1144-1145 in alcohol withdrawal, 1222 Coombs tests, 527-528, 527t COPD. See Chronic obstructive pulmonary disease (COPD). Copper, metabolism of, 651. See also Wilson disease. Cor pulmonale, 244 in chronic obstructive pulmonary disease, 216 Corneal reflection test, 1097-1098 Coronary angiography, 58, 60. See also Cardiac catheterization. in acute coronary syndrome, 110 in angina pectoris, stable, 102, 102t computed tomography compared to, 64f before noncardiac surgery, 277 in non–ST-segment elevation myocardial infarction, 110 in unstable angina, 110 Coronary arteries aneurysms of, in Kawasaki disease, 861 arteritis of, 97-98 atherosclerosis of angiography of, 60 CT angiography of, 63-64, 64f autonomic innervation of, 29 calcification of, 63-64, 64f, 97, 102 collateral vessels of, 23-24 normal anatomy of, 23-24, 23f supplying conduction system, 24 normal variations of, 23-24 Coronary artery anomalies, 82-83 myocardial ischemia caused by, 97-98 Coronary artery bypass grafting (CABG), 158-159. See also Revascularization, coronary. in angina pectoris, 104-105 minimally invasive, 159 noncardiac surgery and, 277 in non–ST-segment elevation myocardial infarction, 110 off-pump, 159 in unstable angina, 110 Coronary artery disease (CAD), 95-117. See also Acute coronary syndromes; Angina pectoris; Atherosclerosis; Cardiovascular disease; Myocardial ischemia. epidemiology of, 95 future prospects for, 117b hypertension and, 174, 175f, 182 magnetic resonance imaging in, 60-61 nonatherosclerotic, 97-98, 106 risk factors for, 96-97, 96t. See also Dyslipidemia. Coronary artery spasm, 99t, 105-106 pain of, 32-33 Coronary artery stenosis angiography of, 60, 96f collateral vessels and, 23-24 pathophysiology of, 95-96 Coronary blood flow, regulation of, 28-29, 98 Coronary circulation exercise and, 31 physiology of, 28-29 Coronary sinus, 23f, 24 Coronary thrombosis in hematologic disorders, 97-98 human platelet antigen-1b and, 582, 582t myocardial infarction caused by, 110 Coronary vasculopathy, in transplanted heart, 160 Corrigan pulse, 36-38 Cortical syndromes, 1068-1071 agnosia, 1070 amnesia, 1070-1071, 1071t anatomical basis of, 1068 aphasia, 1068-1070, 1070t, 1071f apraxia, 1070, 1071f clinical features of, by site of lesion, 1068, 1069f, 1070t Corticobasal-ganglionic degeneration, 1113 Corticosteroid therapy. See also Dexamethasone; Methylprednisolone; Prednisone. for adrenal insufficiency, 665, 683 in alcoholic liver disease, 471-472 in antiphospholipid antibody syndrome, 843

Corticosteroid therapy (Continued) for asthma, 223-224 for autoimmune hemolytic anemia, 527 for bursitis, 875 for chronic obstructive pulmonary disease, 218-219 for drug-induced immune thrombocytopenia, 569 for focal segmental glomerulosclerosis, 328 for giant cell arteritis, 169, 862, 1099 for gout, 867t, 868 for hearing loss, idiopathic, 1103b for Henoch-Schönlein purpura, 860 for hypercalcemia, cancer-associated, 618 for idiopathic inflammatory myositis, 853-854 for immune thrombocytopenic purpura, 569 for inflammatory bowel disease, 436 with calcium and vitamin D, 437 for interstitial lung diseases Churg-Strauss syndrome, 236-237 eosinophilic pneumonia, 239 hypersensitivity pneumonitis, 238 idiopathic pulmonary fibrosis, 230 lymphoid interstitial pneumonia, 231 microscopic polyangiitis, 236 sarcoidosis, 233, 233t Wegener granulomatosis, 236 intra-articular, 827 for calcium pyrophosphate deposition disease, 869 for gout, 867t, 868 in osteoarthritis, 872 for spondyloarthropathies, 832-833 for lymphoma, primary CNS, 1157 for meningitis acute bacterial, 936 tuberculous, 938 for minimal change disease, 327-328 for nephritis acute interstitial, 333 lupus, 326 for Pneumocystis jiroveci pneumonia, 257-258, 1023 for polyarteritis nodosa, 861 for rheumatoid arthritis, 826-827, 827t for shock, 930-932 side effects of adrenal suppression, 682-683 hyperlipidemia, 648t infections, 863 long-term, 827 myopathy, 1189 neutrophil dysfunction, 1030 osteoporosis, 802, 807 purpura, 565-566 for spinal cord compression, 617 for spinal cord edema, tumor-associated, 1157-1158 for Stevens-Johnson syndrome, 947 for superior vena cava syndrome, 618 for systemic lupus erythematosus, 837-839 for Takayasu arteritis, 169, 861 for tendinitis, 875 in traumatic spinal cord injury, 1138 for uveitis, 832 for vasculitis, ANCA-associated, 860 for zoster, 971 Corticotropin-releasing hormone (CRH), 661t, 664, 679, 681f inferior petrosal sinus sampling and, 687 ovine CRH test and, 687 Cortisol, 679-680, 680f in adrenal insufficiency plasma level of, 681-682 replacement of, 683 adrenocorticotropic hormone and, 664-665, 679, 681f, 682 glucose counter-regulation and, 700, 721-722 hypersecretion of. See Cushing syndrome. plasma level of in adrenal insufficiency, 681-682 in Cushing syndrome, 685 diurnal variation in, 685 salivary late-night, 685-687 type 2 diabetes and, 703 urinary free, 685, 687 Cortrosyn-stimulation test, 662t, 665 Corynebacteria, 886 Cost-effectiveness analysis, 17, 19 Costs, medical, 17, 19-20

Index Cosyntropin test, 682 Cough, 193 Cough-variant asthma, 193 Courvoisier sign, 453 COX-2 inhibitors. See Cyclo-oxygenase-2 (COX-2) inhibitors. Coxiella burnetii infection, 912t, 913-914 CPAP. See Continuous positive airway pressure (CPAP). C-peptide, 726, 726t C-peptide suppression test, 724 CpG dinucleotides, methylation of, 5-6, 12 Crack cocaine, 1230 Crackles, 195, 196t Cramps, muscle, 1182-1183 Cranial neuralgias, 1093 Craniopharyngioma, 667 CRB-65 scores, 954t, 958 C-reactive protein as cardiovascular risk factor, 97 in rheumatic disease, 821, 826 Creatine kinase (CK) myocardial necrosis and, 107, 108f myoglobinuria and, 1190 Creatine kinase muscle band (CK-MB) cardiac contusion and, 157 myocardial necrosis and, 107 Creatinine, serum acute kidney injury and, 359b in chronic kidney disease, 369, 372, 372f glomerular filtration rate and, 290-291, 298-299 Creatinine, urine, in acute kidney injury, 362, 362t Creatinine clearance, 290-291, 299, 299t CREST syndrome, 233 Creutzfeldt-Jakob disease, 884-885, 1075, 1163-1164, 1163f CRH. See Corticotropin-releasing hormone (CRH). Crigler-Najjar syndrome, 463 Critical care medicine, 259-265. See also Intensive care unit (ICU). acute respiratory distress syndrome in, 262 acute respiratory failure in, 259-260 drug overdoses in, 264t, 265 future prospects for, 265b gases, fumes, and smoke inhalation in, 264-265, 264t gastrointestinal bleeding in, 417-419 prophylaxis of, 418, 418t hypoglycemia in, 724 mechanical ventilation in. See Mechanical ventilation. myopathy in, 1190 overview of, 259 pneumonia in, 958-959 polyneuropathy in, 1180 shock in, 262-263 systemic inflammatory response syndrome in, 263 Crohn disease, 430. See also Inflammatory bowel disease. causes of, 430-431 clinical features of, 432 diagnosis of, 433, 433f-434f vs. ulcerative colitis, 435-436, 435t differential diagnosis of, 433-434 epidemiology of, 430 extraintestinal manifestations of, 434-435, 435t treatment of, 436-438, 436t Crossover, chromosomal, 8-9, 9f Cryoglobulinemia, 327 Cryoprecipitate, 579 Cryotherapy, for prostate cancer, 765 Cryptococcus neoformans infection, 888 disseminated, 1031-1032, 1032f India ink preparation in, 898, 899f, 938 meningitis in, 888, 938-939, 942 in HIV-infected patients, 1022-1023 Cryptogenic fibrosing alveolitis, 230. See also Pulmonary fibrosis, idiopathic. Cryptogenic organizing pneumonia, 227-231, 228t-229t Cryptorchidism, 691-693 testicular cancer and, 766 Cryptosporidium parvum infection, 981t, 982 in HIV-infected patients, 1024-1025, 1025t Cryptosporidium species, 889t, 1039t Crystal arthropathies, 818, 820f, 864-869. See also Gout. CSF. See Cerebrospinal fluid (CSF).

CT. See Computed tomography (CT). CTA. See Computed tomographic angiography (CTA). Cushing disease, 664-666, 665f, 684-685, 687-688 Cushing syndrome, 684-688 causes of, 684-685, 684t clinical manifestations of, 685, 685t diagnosis of, 685-687, 686f differential diagnosis of, 687 hypertension secondary to, 177t in lung cancer, 268t, 270, 684-685, 687 musculoskeletal manifestations of, 881t subclinical, 690 treatment of, 687-688 Cyanide poisoning, 264t, 265 Cyanosis, 35 Cyclobenzaprine, for fibromyalgia syndrome, 876-877 Cyclo-oxygenase-1 (COX-1), 417, 417f, 559, 827 Cyclo-oxygenase-2 (COX-2), 417, 417f, 827 Cyclo-oxygenase-2 (COX-2) inhibitors adverse effects of, 425 cardiovascular, 559 gastric mucosa and, 417, 425 hepatotoxicity and, 472 nephrotoxicity of, 366 for osteoarthritis pain, 872 platelet function and, 572-573 Cyclophosphamide, 623t bladder toxicities of, 863 for idiopathic inflammatory myositis, 853-854 in reproductive-age women, 863 for rheumatoid arthritis, 827 for systemic lupus erythematosus, 838-839, 843 for systemic sclerosis, 848 for vasculitis, ANCA-associated, 860 Cyclospora cayetanensis, 981t, 982 Cyclosporine, 376-377, 378f for aplastic anemia, 502 for idiopathic inflammatory myositis, 853-854 for inflammatory bowel disease, 436-437 for myelodysplastic syndrome, 505-506 for rheumatoid arthritis, 827 Cyclothymic disorder, 1080 Cystatin C, 299, 363 Cystic fibrosis, 213, 214f, 214t, 221-222, 221t bronchiectasis in, 220-221 Cystic fibrosis transmembrane regulator, 396-397 Cysticercosis, 942, 942f, 1040-1041, 1040t Cystine stones, urinary, 343-344 Cystinosis, 344 Cystinuria, 301, 343-344 Cystitis, 989-991 interstitial, 747 Cystoscopy, in men, 754 Cytokines adipocytokines, 631 as anticancer agents, 627 cellular interactions and, 893 hematopoietic, 496-497, 497t clinical use of, 499 pyrogenic, 910-911, 911f in rheumatoid arthritis, 824 in systemic inflammatory response syndrome, 928t Cytomegalovirus (CMV) infection diarrhea in, in HIV-infected patients, 1025, 1025t encephalitis in, 1023 esophagitis in, 413 in HIV-infected patients, 1021, 1021t fever in, 922 Ménétrier disease caused by, 419 molecular diagnostics in, 901, 902t mononucleosis syndrome in, 912-913, 918-919 in postperfusion syndrome, after heart surgery, 923 retinitis in, in HIV-infected patients, 1019-1020, 1023 D Dactylitis, 829-831 in sickle cell disease, 879 Darbepoetin, for chemotherapy-induced anemia, 627 Dasatinib, 512-513 Dawn phenomenon, 708 DCIS (ductal carcinoma in situ), 610 DDAVP. See Desmopressin (DDAVP).

1247

D-dimer, 559f, 563 in disseminated intravascular coagulation, 571 D-dimer test in deep venous thrombosis, 171 in pulmonary embolism, 172, 242 recurrence risk for thromboembolism and, 589 de Quervain thyroiditis, 674, 950 Dead space, pulmonary, 199-200, 200f Decerebrate posturing, 1060-1062 Decision analysis, 17 Decitabine, 596 for myelodysplastic syndrome, 505 Declarative memory, 1075 Decorticate posturing, 1060-1062 Decubitus ulcers. See Pressure sores. Deep venous thrombosis, 171-174. See also Venous thromboembolism. pulmonary embolism secondary to, 241-243, 242f in traumatic spinal cord injury, 1139 Deep-brain stimulation for dystonia, 1114 for essential tremor, 1114 for Parkinson disease, 1112-1113 Defibrillation, 141 Defibrotide, 486-487 Degenerative joint disease. See Osteoarthritis. Dehydration, hypercalcemia in, 787 Delayed afterdepolarizations, 119 Delirium, 1058-1059, 1202, 1202t, 1206 in palliative care, 1213, 1217 terminal, 1217 Delirium tremens, 1222, 1224 Delta agent, 884 Delta wave, 128f, 129 Delusional disorder, 1081 Delusions, 1081 Dementia, 1072-1076, 1201-1202 cortical vs. subcortical, 1072, 1073t in corticobasal-ganglionic degeneration, 1113 in Creutzfeldt-Jakob disease, 1075, 1163-1164 definition of, 1072 vs. delirium, 1202, 1202t differential diagnosis of, 1072, 1073t in diffuse Lewy body disease, 1074, 1113 in HIV infection or AIDS, 1021-1022, 1022t, 1075 major syndromes of, 1072-1075. See also Alzheimer disease. medical evaluation in, 1072 neuropsychological testing in, 1072 palliative care and, 1211 in progressive supranuclear palsy, 1113 screening for, 1072, 1073t type 2 diabetes and, 722 Demyelinating disorders central nervous system, 1165-1170, 1166t. See also Multiple sclerosis. disseminated encephalomyelitis, acute, 1170 neuromyelitis optica, 1099, 1169 optic neuritis, 1098-1099, 1169 transverse myelitis, acute, 1169-1170 peripheral nervous system, 1175-1176, 1178 Charcot-Marie-Tooth, 1176, 1181 chronic inflammatory demyelinating polyneuropathy, 1180, 1190 Guillain-Barré syndrome, 1176-1177, 1177t, 1179-1180 Denervation, electromyography in, 1171 Deoxyribonucleic acid. See DNA (deoxyribonucleic acid). Depression, 1077-1080, 1079t chronic abdominal pain in, 384-385 dementia and, 1076 in epilepsy, 1141, 1152-1153 in fibromyalgia syndrome, 876 in older adults, 1202-1203 in palliative care, 1213 in perimenopause, 742 postpartum, 739 screening of women for, 734t Dermatitis, in HIV-infected patients candidal, 1020t seborrheic, 1020t Dermatomyositis, 1188-1189, 1189t. See also Myositis, idiopathic. Designer drugs of abuse, 1225t-1228t, 1232-1233

1248

Index

Desmin mutations, in restrictive cardiomyopathy, 153 Desmopressin (DDAVP) for bleeding aspirin-induced, 572 in uremic platelet dysfunction, 573 for diabetes insipidus, 668 for von Willebrand disease, 574-575 Desquamative interstitial pneumonia, 225, 227-231, 228t-229t Devic disease, 1099, 1169 Dexamethasone for cerebral edema with brain abscess, 1159-1160 with brain tumor, 1156 for immune thrombocytopenic purpura, 569 for multiple myeloma, 552 for spinal cord compression, 617 Dexamethasone suppression test, 662t, 665, 685, 687 adrenal incidentaloma and, 690 Diabetes insipidus, 306-307, 311, 667-668, 668t hypothalamic lesions and, 667 water deprivation test in, 299, 668 Diabetes mellitus, 697-720 abbreviations relating to, 697 amyotrophy in, 1180 cardiometabolic risk in, 701 thiazolidinediones and, 713 chronic kidney disease in, 329, 370-371, 370t, 716-717 gluconeogenetic pathway and, 297 insulin requirement and, 297, 374 classification of, 699-701, 700t clinical presentation of, 698 comparison of type 1 and type 2, 700t complications of, 715-720 acute, 715-716, 715t chronic, 716 coronary artery disease and, 97, 116-117 definition of, 697 diagnostic criteria for, 698, 699t diagnostic testing for, 698 epidemiology of, 697-698 erectile dysfunction in, 718, 760 foot care in, 718, 881, 971-972 foot ulcers in, 718, 971-973 osteomyelitis secondary to, 988 future prospects for, 719b-720b, 727b gallbladder disease in, 491-492 gastroparesis in, 427-428, 718 gestational, 698-699, 699t follow-up care with, 739 management of, 706 glucose counter-regulation in, 721-722 glycemic thresholds in, 722 hemochromatosis with, 653-654 hyperlipidemia in, 648t, 649-650, 704 hypertension in, 182, 706, 719 with chronic kidney disease, 370-371 hypoglycemia in cerebral effects of, 722 clinical classification of, 722-725, 723t diagnostic work-up of, 725-726 treatment of, 726-727 unawareness of, 721-722 ketoacidosis in, 698, 715-716, 715t lumbosacral polyradiculopathy in, 1180 management of, 703-715 bariatric surgery in, 633-634, 705 blood glucose monitoring in, 703-704, 704t, 725 elevations of fasting glucose and, 708 exercise in, 705-706 goals in, 703 insulin dosing in, 707-708 insulin injection in, 708 for metabolic syndrome, 715 nutrition in, 704-705 specific treatment goals in, 704, 704t standards of care in, 704 tight control in, 18, 706-707 for type 1, 708 for type 2, 708-715, 710t-713t. See also specific drug classes. weight management in, 705 metabolic syndrome and, 700-701, 715 musculoskeletal manifestations of, 881, 881t

Diabetes mellitus (Continued) myopathy in, 1190 nephropathy in, 329, 716-717 neuropathy in, 718, 881, 1180, 1190 otitis externa in, 945 pancreatitis complicated by, 451 pathogenesis of type 1, 701-702, 701f type 2, 702-703, 702f prevention of, 708, 719-720 retinopathy in, 717-718 risk factors for, 698, 698t screening for, 698-699, 698t sleep apnea with, 245 in stiff-person syndrome, 1188 stress hyperglycemia in, 706-707 subclinical. See Prediabetes. surgical risk and, 274-276, 275t uric acid stones in, 343 in women, 746 Diagnostic tests, 17-19, 17t, 20b Dialysis, 375-376, 376f access for hemodialysis, 376 acquired cystic kidney disease secondary to, 339 in diabetic patient, 717 initiation of, 362, 364, 375 β2-microglobulin–associated amyloidosis and, 880 pericarditis and, 373 peritoneal. See Peritoneal dialysis. protein restriction during, 371, 371t renal osteodystrophy and, 798-799, 800b Diamond-Blackfan anemia, 506 Diaphragm breathing and, 200 paralysis of, 252-253, 253b fluoroscopy of, 210, 252-253 ultrasonography of, 210 Diarrhea, 396-400 acute infectious, 979-984 arthritis secondary to, 829-831, 985 cytotoxin–induced, 979-980 definition of, 979 diagnosis of, 980-981, 983f epidemiologic considerations in, 982 food poisoning, 980 general pathogenesis of, 979 invasive pathogens causing, 980-982, 981t management of, 981t, 982-984, 983f, 984t neurotoxin–induced, 979-980 pathogenesis of, 979 secretory toxin–induced, 979-981 antibiotic-associated. See Clostridium difficile colitis. definition of, 396 diabetic neuropathy with, 718 evaluation of, 398-400 in acute diarrhea, 399, 399f in chronic diarrhea, 399-400, 400f history and physical examination in, 398-399 in HIV-infected patients, 1024-1025, 1025t in inflammatory bowel disease, 437 in irritable bowel syndrome, 384-385 kidney stone formation and, 342 pathophysiologic classification of, 397-398, 397t-398t physiologic basis of, 396-397, 396f-397f traveler’s, 980, 981t, 982, 1036 persistent, 1037 prevention of, 984, 1036 symptomatic therapy for, 984, 1036 Diastole, 22-23, 26-30, 27f Diastolic dysfunction, 28 in hypertrophic cardiomyopathy, 152 in systemic sclerosis, 849 in women, 745-746 Diastolic heart failure, 67 Diastolic rumbles, 43-44 Diatrizoate, 405 Diazoxide, for insulinoma, 724 DIC. See Disseminated intravascular coagulation (DIC). Diclofenac, liver damage caused by, 472 Dicrotic notch, 36-38, 38f Diet. See also Nutritional entries. after acute coronary syndrome, 116-117 in alcoholic liver disease, 471-472 cancer risk and, 599

Diet (Continued) in chronic kidney disease, 371, 371t for diabetic patients, 704-705 in diarrhea, 984t in dyslipidemia, 646, 646t for gout patient, 868 for hypoglycemia management, 726-727 ketogenic, for epilepsy, 1150 nephrolithiasis and, 342, 342t for weight loss, 632, 632t Diffuse aggressive non-Hodgkin lymphomas, 545, 553 Diffuse alveolar hemorrhage, 235-237 Diffuse esophageal spasm, 411, 412f, 412t Diffuse idiopathic skeletal hyperostosis, 881 Diffuse infiltrative lymphadenopathy syndrome, in HIV infection, 856-857 Diffuse large B-cell lymphoma, 545 chronic lymphocytic leukemia transforming to, 548 in HIV-infected patient, 553 Diffuse Lewy body disease, 1074, 1113 Diffuse panbronchiolitis, 219-220 Diffusion capacity for carbon monoxide (Dlco), 195-197, 209 in asthma, 223 in chronic obstructive pulmonary disease, 217 in interstitial lung diseases, 226 preoperative, in lung cancer, 270-271 Diffusion impairment, alveolar, 206 Diffusion tensor imaging, 1071b Digestion, 390 of carbohydrates, 389 of fat, 389 of proteins, 389 Digital ulcerations, in systemic sclerosis, 847-848, 848t Digoxin as antiarrhythmic agent, 139 electrocardiogram and, 53, 54f in heart failure, 72-73 Dihydrotestosterone, 752 1,25-Dihydroxyvitamin D, 292 tumor secretion of, 785 Dilated cardiomyopathy, 149-151, 150t in Chagas disease, 148 echocardiography in, 71f implantable cardioverter-defibrillator in, 142-143 myocarditis resulting in, 148, 150 peripartum, 164 Diltiazem, in dilated cardiomyopathy, idiopathic, 72 Dip-and-plateau sign, in constrictive pericarditis, 147-148, 148f Dipeptidyl peptidase-4 inhibitors, 710t-713t, 715 Diphtheria, 949 immunization of travelers against, 1035 Diplopia, evaluation of, 1097-1098 Dipyridamole, aspirin with, for stroke prevention, 1132 Dipyridamole stress testing, 55 before noncardiac surgery, 276 Direct renin inhibitors, 179t-182t Direct thrombin inhibitors, in heparin-induced thrombocytopenia, 586 Disease-modifying antirheumatic drugs (DMARDs), for rheumatoid arthritis, 827, 827t Disease-modifying genes, 12 Disopyramide, in hypertrophic cardiomyopathy, 152 Disseminated intravascular coagulation (DIC), 570-571, 571t cryoprecipitate for, 579 in malignancies, 585 microangiopathic hemolysis caused by, 528 in sepsis, 929 Dissociative drugs, 1225t-1228t, 1231-1232 Distal convoluted tubule, 293-294, 294f functions of, 293-294, 294f structure of, 287f, 289-290 Distal nephron functions of, 293-295, 294f-295f in acid-base balance, 316-317, 317f potassium secretion and, 294-296 water reabsorption and, 296 inherited salt-wasting syndromes and, 314-316 structure of, 286-290, 287f-288f Disulfiram (Antabuse), 1223

Index Diuretics. See also Loop diuretics; Thiazide-type diuretics. contraindications to, 181t-182t in heart failure, 72 refractory, 73 for hyperkalemic renal tubular acidosis, 320 for hypertension, 179-180, 179t-180t, 182, 184 hypokalemia caused by, 314 hypomagnesemia caused by, 794 mechanisms of action, 292-295, 307-308, 308t metabolic alkalosis secondary to, 321 in pulmonary arterial hypertension, 170 side effects of, 181t-182t Dix-Hallpike test, 1105 Dizziness, 1104-1107 evaluation of, 1104-1107 presentations of, 1104, 1105t treatment of, 1107 Dlco. See Diffusion capacity for carbon monoxide (Dlco). DMARDS. See Disease-modifying antirheumatic drugs (DMARDs). DNA (deoxyribonucleic acid), 2 methylation of, 5-6, 12 in molecular diagnostics, 900, 901f, 902t transcription of information in. See Transcription. DNA methyltransferase inhibitors, for myelodysplastic syndrome, 505 DNA microarrays, 11, 13, 14b DNA polymerase, tandem repeats and, 9 DNA repair genes, 596 DNAase I, 6 Dobutamine, for heart failure after myocardial infarction, 114-115 refractory, 73 Dobutamine stress echocardiography, 55 before noncardiac surgery, 276 Dobutamine stress magnetic resonance imaging, 276 Dofetilide, 137t-138t, 139 Doll’s eyes maneuver, 1061-1062 Domestic violence, 747-748, 748t Dominant mutation, 11t, 12 Domperidone, for gastroparesis, 428 Dopamine for heart failure after myocardial infarction, 114-115 refractory, 73 prolactin and, 661t Dopamine agonists, 1112, 1112t. See also Cabergoline. for acromegaly, 662-663 for prolactinoma, 663 for restless legs syndrome, 1067, 1067t Doppler echocardiography, 55-57, 56f-57f in restrictive cardiomyopathy, 154t Doppler ultrasonography of acute scrotum, 769 duplex of aortic and iliac aneurysms, 167-168 in deep venous thrombosis, 171 in peripheral arterial disease, 166 in renal artery stenosis, 347-348 in peripheral arterial disease, 65 of renal vein thrombosis, 356-357 transcranial, 1056 Double contrast, 405 Down syndrome, dementia in, 1072-1073 Doxazosin, for benign prostatic hyperplasia, 754-755 Doxorubicin, 623t Dravet syndrome, 1142, 1150 DRE. See Rectal examination (DRE). Drop seizures, 1146, 1153 Drosha, 5 Drotrecogin alfa, for septic shock, 262 Drug abuse. See also Infective endocarditis, in intravenous drug users. arterial injection in, infection secondary to, 968 heat stroke caused by, 1084 illicit drugs in, 1224, 1225f, 1225t-1228t, 1230-1233. See also Cocaine; Heroin; Marijuana. prescription drugs in, 1224-1230, 1225t-1228t pulmonary effects of, 234 Drugs acute interstitial nephritis caused by, 333, 334t bone loss associated with, 802-804 cholestasis caused by, 463-464, 464b

Drugs (Continued) in chronic kidney disease, 371-372, 372t diabetes caused by, 700 erectile dysfunction induced by, 761, 761t fever associated with, 910-911, 922-923 hearing loss caused by, 1102 hemolysis induced by, 527, 527t, 529 hepatitis caused by, 472-473, 472t hypercalcemia caused by, 786 hyperthermia associated with, 1083-1084 hypocalcemia caused by, 788t, 790 hypoglycemia caused by, 723-724 hypophosphatemia caused by, 792 immune thrombocytopenia caused by, 569, 570t with heparin, 586 lung diseases induced by, 234-235, 235t muscle damage caused by, 1190, 1190t myasthenic syndromes induced by, 1193 neutropenia induced by, 537 in older adults, 1201 overdoses of, 264t, 265 platelet dysfunction caused by, 572-573, 572t porphyria triggered by, 654, 655t, 656-657 in pregnancy, 738-739, 738t-739t renal excretion of, 296 tremor provoked by, 1114 xerophthalmia and xerostomia caused by, 857 Dual-energy x-ray absorptiometry, 795, 800, 804-805, 806f, 807t Ductal carcinoma in situ (DCIS), 610 Ductus arteriosus, patent, 76f, 76t, 80 Duke criteria, for infective endocarditis, 963, 964t Dumping syndrome, 428, 725 Duodenoscope, 402-404 Duodenum, 414-429 anatomy of, 414-415, 415f biopsy of, 391 digestion in, 390 endoscopy of, 401 gastronomas in, 426-427 motor physiology of, 416 ulcers of. See Peptic ulcer disease. Dutasteride, for benign prostatic hyperplasia, 755 Dying process, 1216-1217 Dysarthria, 1070 Dysautonomia, in traumatic spinal cord injury, 1139 Dysbetalipoproteinemia, familial, 649 Dysdiadochokinesis, 1111t, 1116 Dysfibrinogenemia, 575-579 arterial thrombosis and, 582t, 587 Dysgerminoma, 1,25-dihydroxyvitamin D secretion by, 785 Dyskeratosis congenita, 500-501 Dyskinesia, 1111t Dyslipidemia, 643. See also Hypercholesterolemia. in chronic kidney disease, 369-370, 374-376 definition of, 644-645 in diabetes mellitus, 648t, 649-650, 704 diagnosis of, 644-645 future prospects for, 650b genetic disorders with, 648-650 management of, 646-647, 646t-647t in coronary artery disease, 102, 116-117 metabolic syndrome and, 700-701 screening for, 645, 645t recommendation for women, 734t secondary causes of, 648, 648t therapeutic approach to, 645-646, 646t Dysmetria, 1111t Dyspepsia evaluation of, 422f nonulcer, 384, 422f, 425-426 Dysphagia, 408, 410-413, 411f in esophageal carcinoma, 439, 606 in idiopathic inflammatory myositis, 851 imaging studies in, 405 sideropenic, 412 Dysphasia. See Aphasia. Dysphonia, spasmodic, 1115t Dyspnea in cardiac disease, 33 with heart failure, 69-71 causes of, 193t paroxysmal nocturnal, 33, 69-70, 192 in respiratory disease, 192, 193t

1249

Dysprosody, 1068-1070 Dysrhythmokinesis, 1111t, 1116 Dyssynergia, 1111t Dysthymic disorder, 1077-1078 Dystonia, 1111t, 1114, 1115t Dystrophin-glycoprotein complex, 1182, 1183f, 1184 E Ear infections, 945 subdural empyema secondary to, 1160-1161 Early afterdepolarizations, 119 Early repolarization, 51-53 Eating disorders, 635-637, 736 potassium imbalance in, 314 refeeding in, 793 Eaton-Lambert syndrome, 268t, 270, 619t EBCT (electron-beam computed tomography), of coronary calcification, 97, 102 Ebstein anomaly, 78t, 79 EBV. See Epstein-Barr virus (EBV) infection. ECF. See Extracellular fluid (ECF). ECG. See Electrocardiography (ECG). Echinococcus, 1040t, 1041 Echocardiography, 40-42, 56f-58f of aortic stenosis, 84-85 of atrial septal defect, 76-77 contrast agents in, 56-57, 57f in dilated cardiomyopathy, 151 Doppler. See Doppler echocardiography. in heart failure, 70-71, 71f after myocardial infarction, 115 in hypertrophic cardiomyopathy, 152-153 in infective endocarditis, 963, 964t in mitral regurgitation, 90 of mitral stenosis, 88-89, 88f of mitral valve prolapse, 89f, 90-91 in myocarditis, 149 of pericardial effusion, 146-147 in pericarditis, constrictive, 147-148 in pulmonary arterial hypertension, 170 in pulmonary embolism, 172-173 in pulmonary hypertension, idiopathic, 243 in restrictive cardiomyopathy, 154t in tamponade, 147 transesophageal. See Transesophageal echocardiography (TEE). Eclampsia, 184, 351 hypermagnesemia caused by treatment of, 793 Ecstasy, 1232-1233 heat stroke caused by, 1084 Ecthyma gangrenosum, 929, 970, 970t Eculizumab, for paroxysmal nocturnal hemoglobinuria, 502-503, 529, 585 Edema, 35. See also Volume disorders. cerebral. See Cerebral edema. in glomerular disease, therapy of, 325 in heart failure, 69-71 diuretics and, 72 in hypothyroidism, 675 pulmonary. See Pulmonary edema. Edrophonium, in anticholinesterase test, 1191-1192 Efalizumab, central nervous system infections and, 942-944, 943t Effective circulating volume (ECV), 306-307, 306f, 307t Effusive constrictive pericarditis, 148 EGF. See Epidermal growth factor (EGF). Egophony, 195 Ehlers-Danlos syndrome, 566 Ehrlichiosis, 885, 916-917 Eisenmenger syndrome, 82 atrial septal defect with, 76 patent ductus arteriosus with, 80 ventricular septal defect with, 77 Ejection fraction, left ventricular (LVEF), 28 in heart failure, 66-68, 73 diuretics and, 72 preserved, 67-68, 72 resynchronization therapy and, 68 measurement of by contrast ventriculography, 60 by ECG-gated perfusion imaging, 57-58 by radionuclide ventriculography, 57 Ejection sounds, 41, 42f

1250

Index

Elastin, mutations of, supravalvular aortic stenosis caused by, 78-79 Elder abuse, 1205 Elderly patients. See Older adults. Electrocardiography (ECG), 46-49 ambulatory monitoring with, 53 in arrhythmias, 132-133 before noncardiac surgery, 276 in angina pectoris, 99-102, 99t, 100f-101f in arrhythmia evaluation, 131-132 in arrhythmogenic right ventricular cardiomyopathy/ dysplasia, 154-155 in atrial abnormalities, 50, 50t of atrial premature complexes, 120, 121f with atrial septal defect, 76t in atrial tachyarrhythmias, 124-126, 125f in atrioventricular block, 122-123, 124f in atrioventricular nodal (junctional) rhythm disturbances, 127-128, 128f in bundle branch block, 50-51, 50t, 51f drug influences on, 53, 54f with event recorder, 53, 132-133 in fascicular block, 50-51, 50t in heart failure, 70 horizontal scale of, 46 in hypercalcemia, 53, 54f in hyperkalemia, 312-313, 364 in hypertrophic cardiomyopathy, 152 in hypocalcemia, 788 of junctional premature complexes, 121, 121f leads in, 47-49, 48f in left ventricular hypertrophy, 50, 50t metabolic influences on, 53, 54f in myocardial infarction, 51-53, 52f-53f infarct localization with, 53, 54t, 106-107 non–ST-segment elevation, 108, 108f, 110 right ventricular, 115, 115f ST-segment elevation, 106-107, 107f, 110 in myocardial ischemia, 51-53 during exercise, 55 normal waves and intervals in, 46-47, 47f with nuclear myocardial perfusion imaging, 58 in pericardial effusion, 146 in pericarditis, acute, 145 postoperative, myocardial infarction and, 280 preoperative, 274 pressure tracings associated with, 27f in pulmonary embolism, 172, 242 in restrictive cardiomyopathy, 154t in right ventricular hypertrophy, 50, 50t in seizure evaluation, 1148 stress testing with, 53-55 in syncope evaluation, 134 in trauma, 157 in unstable angina, 99t, 108, 110 in valvular heart disease, acquired, 86t in variant angina, 51-53, 99t, 105, 106f of ventricular fibrillation, 130f, 131 of ventricular premature complexes, 121-122, 121f of ventricular tachycardia, 130, 130f vertical scale of, 46 Electroconvulsive therapy, 1079-1080 Electroencephalography, 1055-1056 brain death and, 1063t in seizure diagnosis, 1147 of absence seizure, 1145-1146, 1145f of absence status epilepticus, 1151 inpatient video monitoring in, 1147 of juvenile myoclonic epilepsy, 1146 of Lennox-Gastaut syndrome, 1146 Electrolytes. See Bicarbonate; Chloride; Magnesium; Phosphate; Potassium; Sodium. Electromyography, 1055-1056, 1171 in idiopathic inflammatory myositis, 853, 853t in myasthenia gravis, 1192 in peripheral neuropathies, 1178 Electron-beam computed tomography (EBCT), of coronary calcification, 97, 102 Electrophysiologic studies, neurologic, 1055-1056 Electrophysiologic testing, cardiac, 133-134 Elemental diets, in small bowel Crohn disease, 437 Elephantiasis, 1040 ELISA (enzyme-linked immunosorbent assay), 900f Elliptocytosis, hereditary, 528, 528t Eltrombopag, 499

Embolism arterial. See Arterial embolism. venous. See Venous thromboembolism. Emphysema, 190-191, 213-215, 214f, 214t. See also Chronic obstructive pulmonary disease (COPD). α1-antitrypsin deficiency and, 215-216 definition of, 215 epidemiology of, 189-190 lung compliance in, 201, 201f small airways and, 216 surgery for, 219 Empty sella syndrome, 660, 1092 Empyema, 249-250, 256, 959 subdural, 1160-1161 tuberculous, 250 Encephalitis, 933-934, 940. See also Central nervous system infections; Meningoencephalitis. immune response modifiers implicated in, 942-944, 943t rabies, 941 Toxoplasma, 942, 943f in HIV-infected patients, 1022, 1023t Encephalomyelitis, acute disseminated, 1170 Encephalomyopathy, mitochondrial, with lactic acidosis and stroke-like episodes (MELAS), 1187 Encephalopathy hypertensive, 184-185, 1131 metabolic, 1058, 1059t physical examination in, 1060-1061 myoclonic, 1115-1116 Wernicke, 1071, 1224 hypothermia in, 1083 Endarteritis, bacterial, 967-968 Endobronchial ultrasound, 211 Endocannabinoid receptor antagonist, 633 Endocannabinoids, 719b-720b appetite and, 631 Endocarditis in antiphospholipid antibody syndrome, 841 infective. See Infective endocarditis. marantic, 571, 963 in Trousseau syndrome, 171 subacute bacterial, glomerulonephritis secondary to, 326 in systemic lupus erythematosus, 835 End-of-life care in chronic obstructive pulmonary disease, 219 palliative. See Palliative cancer treatment; Palliative care. Endolymphatic hydrops, 1102 Endometrial biopsy, 741-742 Endometrial cancer, 613 Endometriosis, pneumothorax secondary to, 250 Endomyocardial biopsy, 60 in myocarditis, 149 Endomyocardial fibrosis, restrictive cardiomyopathy in, 153-154 Endoscopes, 401-404, 402f Endoscopic retrograde cholangiopancreatography (ERCP), 402-403, 404f in acute cholangitis, 493 in acute pancreatitis, 450 with gallstones, 493 in chronic pancreatitis, 451-452 intraoperative, in cholecystectomy, 491 in pancreatic carcinoma, 453 in primary sclerosing cholangitis, 493, 493f Endoscopic ultrasound, 403-404, 404f of biliary disorders, 494b in chronic pancreatitis, 451-452 of colorectal carcinoma, 442 of esophageal carcinoma, 440, 606 of gallstones, 491 of gastric malignancies, 441 in jaundice evaluation, 464b of pancreatic carcinoma, 453 Endoscopy, gastrointestinal, 401-404, 403f-404f. See also Video capsule endoscopy. for bleeding, 387-388 variceal, 481 video capsule for, 402 of colon. See Colonoscopy; Sigmoidoscopy. of esophageal carcinoma, 440 of esophageal obstruction, 411 of esophageal rings, 412

Endoscopy, gastrointestinal (Continued) of esophageal ulcers, 413 future prospects for, 407b in gastroesophageal reflux disease, 409-410 in gastroparesis, 428 in nonulcer dyspepsia, 425 in peptic ulcer disease, 421-423, 423f vs. upper GI series, 405 Endothelial cells of glomerular capillaries, 289 hemostasis and, 555-556, 556t, 558, 561 thrombosis and, 580 Endothelial dysfunction in acute kidney injury, 365 in atherosclerosis, 95, 98 coronary artery, 29 erectile dysfunction and, 760 in metabolic syndrome, 700-701 in preeclampsia, 351-352 in type 2 diabetes, 703 Endothelin in coronary arteries, 29 renal water reabsorption and, 296 Endothelin receptor blockers, for pulmonary arterial hypertension, 170 Endothelium and coronary artery blood flow, 29 and systemic blood flow, 29 Endothelium-derived relaxing factor, 29. See also Nitric oxide. End-stage renal disease (ESRD). See also Chronic kidney disease (CKD). in Alport syndrome, 330 cardiovascular mortality in, 373 care of patient with, 375-379. See also Dialysis; Kidney transplantation. causes of, 369, 370t definition of, 369 in diabetes, 329, 716-717 in focal segmental glomerulosclerosis, 328 in HIV-associated nephropathy, 1026 in hypertensive nephrosclerosis, 331 in juvenile nephronophthisis, 339 in lupus nephritis, 326 β2-microglobulin accumulation in, 373 in polycystic kidney disease autosomal dominant, 337-338 autosomal recessive, 338-339 porphyria cutanea tarda in, 656-657 rate of decline to, 372, 372f Energy requirements, 639 Enhanced automaticity, 119 Enhancer sites, 3f, 5-6 Enoxaparin, in unstable angina or non–ST-segment elevation myocardial infarction, 109-110 Entacapone, 1112, 1112t Entamoeba histolytica infection, 889t, 1038, 1039t hepatic abscess in, 975-976 intestinal syndromes in, 981t, 982, 984 Enteral nutrition, 640. See also Tube feeding. hypercalcemia associated with, 787 Enteric fever, 913 Enterobacteriaceae, 886 Enterobiasis, 1038-1039, 1040t Enteroclysis, 405 computed tomographic, 406 Enterococci, 886-887 Enterography, computed tomographic, 406 in Crohn disease, 433 Enterohepatic circulation, 389-390, 488 Enteroscopy, 402 Enteroviral infections, 912, 912t meningitis, 937 laboratory diagnosis of, 902t, 937 Enthesitis, in spondyloarthropathies, 829-833, 830t Enthesopathy, 818, 820f, 875 Environmental agents. See Toxins. Enzyme-linked immunosorbent assay (ELISA), 900f Enzymes, cardiac in acute coronary syndromes, 106-108, 108f, 110 in myocarditis, 149 Eosinophilia differential diagnosis of, 535, 535t in returning traveler, 1037, 1040 Eosinophilia-myalgia syndrome, 847t

Index Eosinophilic esophagitis, 412-413 Eosinophilic fasciitis, 847, 847t Eosinophilic folliculitis, in HIV-infected patients, 1020t Eosinophilic gastritis, 418 Eosinophilic granuloma. See Langerhans cell histiocytosis. Eosinophilic lung diseases, 239-240 Eosinophils normal structure and function of, 534-535, 534f progenitors of, 497-498, 498f Eosinophiluria, 300 Ependymoma, 1157 Epicardium, 22 Epidermal growth factor (EGF), magnesium transport and, 316 Epidermal growth factor receptor (EGFR) breast cancer and, 610 lung cancer and, 266, 269, 625-626 Epidermal growth factor receptor (EGFR) antagonists, 625, 626t Epididymitis, 768 Epidural abscess spinal, 987, 1161-1162, 1161f subdural empyema with, 1160 Epigenetic control of gene expression, 4, 6 Epiglottitis, 949 Epilepsy, 1141-1153. See also Seizure(s). activity restrictions in, 1141, 1150, 1153 benign rolandic, 1144-1145 causes of, 1141-1142, 1142f classification of, 1141, 1143 definition of, 1141 diagnosis of, 1147-1148 differential diagnosis of, 1148-1149, 1148t future prospects for, 1153b generalized idiopathic (primary), 1146, 1149-1150 symptomatic, 1146-1147, 1150-1151 genetics of, 1142, 1144-1146, 1151 incidence and prevalence of, 1141 ketogenic diet for, 1150 myoclonic, 1115-1116 with ragged red muscle fibers, 1187 nocturnal, 1141 partial, 1144-1145, 1149-1151 post-traumatic, 1145 pregnancy in woman with, 1151-1152 prognosis of, 1153 psychosocial concerns in, 1141, 1152-1153 seizure threshold in, 1141 status epilepticus, 1151, 1152t nonconvulsive, 1058 surgery for, 1150 vs. symptomatic seizures, 1141 treatment of, 1149-1151, 1150t. See also Antiepileptic drugs. vagus nerve stimulator for, 1150-1151 Epinephrine, glucose counter-regulation and, 721-722 Episcleritis, inflammatory bowel disease with, 435 Epistaxis, vs. hemoptysis, 193 Eplerenone, for adrenal hyperplasia, 177-178 EPO. See Erythropoietin (EPO). Epoprostenol, for pulmonary hypertension arterial, 170 in systemic sclerosis, 848-849 Epsilon wave, in arrhythmogenic right ventricular cardiomyopathy/dysplasia, 154-155 Epstein-Barr virus (EBV) infection central nervous system lymphoma in, primary, 1022, 1023t fever in, 922 hemolytic anemia associated with, 527-528 Hodgkin disease and, 546 mononucleosis syndrome in, 912-913, 917-918 pharyngitis in, 948 non-Hodgkin lymphomas and, 542-543 Burkitt lymphoma, 545-546 in HIV-infected patient, 553, 1026 oral hairy leukoplakia in, 1020 post-transplantation lymphoproliferative disorder and, 553 Eptifibatide, 582 ERCP. See Endoscopic retrograde cholangiopancreatography (ERCP).

Erectile dysfunction, 759-763 causes of, 760-761, 761t in diabetes mellitus, 718, 760 in peripheral arterial disease, 38, 165-166, 760-761 prevalence of, 759, 759t prostate cancer treatment and, 764-765 treatment of, 761-763, 762f Erection, penile, mechanism of, 759, 760f Erlotinib, 626t for lung cancer, 269 Erysipelas, 972 Erythema migrans, 972-973, 972t Erythema multiforme, oral lesions in, 947 Erythema nodosum in inflammatory bowel disease, 435 in sarcoidosis, 882 Erythrocyte sedimentation rate, in rheumatic disease, 821, 826 Erythrocytes. See Red blood cells (RBCs, erythrocytes). Erythrocytosis causes of, 507-508, 508t paraneoplastic, 619t Erythromelalgia, in essential thrombocythemia, 509, 585-586 Erythromycin for gastroparesis, 428 mechanism of action, 4 Erythropoietic porphyria, 655f, 656t, 657 Erythropoietin (EPO), 497t, 499 in anemia, 526 for anemia of chronic disease, 526 for chemotherapy-induced anemia, 627 chronic kidney disease and, 374 for myelodysplastic syndrome, 504 polycythemia vera and, 508 renal production of, 297 Escape beat, 118 Escape rhythm, 118 Escherichia coli enterohemorrhagic, 980-981 enteroinvasive, 981 enterotoxigenic, 980, 982 in travelers, 1036 hemolytic uremic syndrome and, 354, 587 Esomeprazole for peptic ulcer disease, 423-424 for stress bleeding prophylaxis, 418 Esophageal carcinoma, 410, 439, 606-607, 607t Esophageal disorders, 408-413 dysphagia, 408, 410-413, 411f in esophageal carcinoma, 439 in idiopathic myositis, 1188 imaging studies in, 405 sideropenic, 412 eosinophilic esophagitis, 412-413 gastroesophageal reflux and. See Gastroesophageal reflux disease (GERD). HIV-associated esophagitis, 1021, 1021t infections, 413 motility disorders, 411-412, 412f, 412t dysphagia in, 411 reflux and, 409 pill esophagitis, 413 rings and webs, 411-412 symptoms of, 408-409 Esophageal manometry, 411-412, 412t Esophageal pH monitoring, ambulatory, 409-410 Esophageal sphincter, lower, 414 agents affecting, 415f Esophagogastroduodenoscopy, 401, 403f Esophagus, normal function of, 408 ESRD. See End-stage renal disease (ESRD). Essential tremor, 1109, 1114 Estradiol, gonadotropins and, 666 Estrogen bone loss and, 743, 745, 802-804 menstrual cycle and, 732f, 733 osteoarthritis and, 870 topical vaginal, 744 Estrogen agonists-antagonists, 808-809, 808t Estrogen receptors, 733 in breast cancer, 6 Estrogen replacement therapy. See Hormone replacement therapy.

1251

Etanercept, 13 alcoholic liver disease and, 471-472 central nervous system infections and, 942-943, 943t for rheumatoid arthritis, 827, 827t for spondyloarthropathies, 832 Ethosuximide, 1149, 1150t Ethylene glycol toxicity, 366 Etidronate, for Paget disease of bone, 814-815, 815t Euthyroid sick syndrome, 676 Evans syndrome, 568-569, 841-842 Event recorder, 53 in arrhythmias, 132-133 Evidence-based medicine, 16-20 costs and, 17, 19-20 diagnostic tests in, 17-19, 17t, 20b evaluating treatments in, 18 future challenges in, 20b Internet resources for, 18-19, 19t introduction to, 16 patient involvement in, 19 quality of life and, 19-20 screening tests in, 17, 17t, 19, 20b types of evidence in, 16-17, 17t Evoked potentials, 1055-1056 in multiple sclerosis, 1166, 1167t Exenatide, 710t-713t, 714 Exercise. See also Physical activity. after acute coronary syndrome, 116-117 for angina patients, 102-103 cardiovascular response to, 30-31, 30t coronary artery disease and, 97 for diabetic patients, 705-706 in dyslipidemia management, 646 in fibromyalgia syndrome, 876-877 for osteoporosis prevention, 807 in peripheral arterial disease, 166 in rheumatoid arthritis, 826-828 for weight loss, 632, 632t Exercise testing. See Cardiopulmonary exercise testing; Stress testing. Exercise tolerance, preoperative, 274-276, 275t Exons, 3, 3f Expressed prostatic secretions, 757-758 External counterpulsation in heart failure, 72 for refractory angina, 105 Extracellular fluid (ECF), 305, 306f calcium homeostasis and, 772-775, 773f depletion of, 306-307 homeostasis of, 305-306, 307t magnesium homeostasis and, 781, 782f osmolality of, 308-309, 309f phosphate homeostasis and, 779-780, 779f Extramedullary hematopoiesis, 496 in primary myelofibrosis, 510-511 Extrapyramidal system, 1109, 1110f-1111f, 1110t Extrinsic allergic alveolitis. See Hypersensitivity pneumonitis. Eye movements evaluation of, 1097-1098 intracerebral hemorrhage and, 1133t ophthalmoplegia, 1098, 1098t progressive external, 1187 reflex, in coma, 1058, 1059f, 1061 Ezetimibe, 395, 647 F Fabry disease, 331, 1176t Factitious disorder, 1082 Factor V Cambridge mutation, 583 Factor V deficiency, 576 Factor V Leiden mutation, 582-585, 582t, 587 Factor VIII acquired inhibitors of, 577 liver disease and, 577 virally inactivated concentrate, 579 Factor X deficiency, 576 Factor Xa inhibitor. See Fondaparinux. Factor XI deficiency, 576 Factor XIII deficiency, 577-578 Fall prevention, 807, 1203, 1204t Familial adenomatous polyposis, 441-442, 608 Familial fatal insomnia, 884-885, 1163

1252

Index

Familial hypocalciuric hypercalcemia, 775-776 Famotidine, for peptic ulcer disease, 423 Fanconi anemia, 500-501, 567 Fanconi syndrome, 319 in interstitial nephritis, 334t, 335 in Wilson disease, 651 Fascicular block electrocardiography in, 50-51, 50t in myocardial infarction, 114 Fasciculations, 1171-1172 Fasciitis eosinophilic, 847, 847t necrotizing, 973-974 Fast, 72-hour, 724-726, 724t, 726t Fasting hypoglycemia, 723-725, 723t-724t Fasting plasma glucose, 698, 699t, 703-704 Fatigue in cardiac disease, 35 in heart failure, 69-70 in motor system disease, 1108 in muscle disease, 1182-1183 in systemic lupus erythematosus, 835 Fats digestion and absorption of, 389, 643 malabsorption of, 390-391, 393-394, 398 Fatty acids free, 643-644, 644f metabolic disorders of, 1186-1187, 1186t Fatty liver, 474 alcoholic, 471-472 in metabolic syndrome, 700-701 Fatty streak, 95 Febrile neutropenia, 616-617, 627, 920t, 923 fungal infection in, 1032 prevention of infections in, 1032-1033 treatment of infections in, 1033 Febrile seizures, 1147, 1150 Febuxostat, for gout, 868 Fecal fat analysis, 391, 393-394, 451 Fecal sample. See Stool sample. Fecal water, osmotic gap in, 393-394 Felbamate, 1150 Felty syndrome, 537, 825-826 Fenoldopam, in hypertensive emergency, 185, 185t Fentanyl, 1214t abuse of, 1225t-1228t, 1229 illicit analogs of, 1232 Ferritin, 653-654, 653t Fetal alcohol spectrum disorders, 1224 Fetal loss, maternal thrombophilia and, 584-585 FEV1. See Forced expired volume in 1 second (FEV1). Fever, 910-924 acute syndromes with, 911-920 with fever only, 911-915, 912t future prospects for, 924b with lymphadenopathy, 917-920, 918t with rash, 915-917, 915t after animal exposure, 912t, 913-914 back pain with, 987 deleterious effects of, 911 factitious, 923-924 future prospects for, 924b headache with, 1091 vs. hyperthermia, 910 neutropenia with. See Febrile neutropenia. pathogenesis of, 910-911, 911f patterns of, 911 pneumonia with pleural effusion and, 959 in returned traveler, 1037 in sepsis syndrome, 928-929 in traumatic brain injury, 1137-1138 of unknown origin, 920-923, 920t-921t factitious, 923-924 in HIV-infected patients, 920-923, 920t, 1025 immune-deficient, 920t, 923 nosocomial, 920t, 923, 993 urinary tract infection with, 990 Feverfew, for migraine prevention, 1088 Fiber, dietary, for diabetic patient, 705 Fibric acid derivatives, 647, 647t in diabetes, 704 in stable angina, 102 Fibrillation, 1171 Fibrin clot, 562-563

Fibrin split products, 580-581 in disseminated intravascular coagulation, 571 Fibrinogen disorders, 575-579 dysfibrinogenemia, 575-579 arterial thrombosis and, 582t, 587 Fibrinogen level, thrombin time and, 564, 565t Fibrinolytic system, 559f, 562-563, 580-581 disordered, in metabolic syndrome, 700-701 Fibrinolytic therapy. See Thrombolytic therapy. Fibroblast growth factor-23, 292, 781 hypophosphatemic rickets and, 792-793 tumoral calcinosis and, 791-792 tumor-induced osteomalacia and, 792-793 Fibroelastoma, cardiac, 156 Fibroma, cardiac, 156 Fibromuscular dysplasia, 177, 178f, 348, 348t, 349f Fibromyalgia syndrome, 873, 875-877, 876t Fick method, of cardiac output measurement, 59-60 Figure-4 sign, 1144 Filariasis, lymphatic, 1040 Filgrastim, 627 Filling pressures. See also Pressures, intracardiac, measurement of. atrial left, 26-27, 27f, 27t right, 26-27, 27t, 36 ventricular, 26-27, 27f, 27t Filter paper test, for keratoconjunctivitis sicca, 856 Filtration fraction, renal, 292 Finasteride, for benign prostatic hyperplasia, 755, 756t Fine-needle aspiration, with endoscopic ultrasound guidance, 403-404 FISH (fluorescent in situ hybridization), 11 Fitz-Hugh-Curtis syndrome, 976, 1003 5q–syndrome, 503-504, 504t-505t, 506 Fleischer sign, 242 Flow-volume loops, 208-209, 208f Fludrocortisone, for mineralocorticoid deficiency, 683 Fluid compartments, 305, 306f Fluid disorders of osmolality, 308-309 of volume, 306-308, 307t Fluid management distribution of infused fluid, 307 at end of life, 1216-1217 in gastrointestinal bleeding, 386-387 in hypercalcemia, 618 in infectious diarrhea, 982-983, 983f, 984t in sepsis syndrome, 930 in traumatic brain injury, 1137 in traumatic spinal cord injury, 1138-1139 Flumazenil, for benzodiazepine overdose, 1228 Flunitrazepam, 1225-1228, 1225t-1228t Fluorescent in situ hybridization (FISH), 11 Fluoroscopy, of diaphragm paralysis, 210, 252-253 5-Fluorouracil, 623t Fluticasone, in chronic obstructive pulmonary disease, 218-219 Foam cells, 95, 643-644 Focal glomerular sclerosis, podocytes and, 288-289 Focal segmental glomerulosclerosis, 328, 328f, 328t Focal seizures. See Seizure(s), partial. Folic acid (folate) deficiency of, 525-526, 525t metabolic pathways of, 524, 524f supplementation of, for women, 737, 739, 1119 with epilepsy, 1152 Follicle-stimulating hormone (FSH), 660, 662t, 666 in male, 691, 692f menstrual cycle and, 732f, 733 perimenopause and, 742 Follicular lymphomas, 542, 544-545 Folliculitis, 969, 970t in HIV-infected patients, 1020t Fondaparinux for deep venous thrombosis, 171 for prophylaxis of venous thromboembolism, 173-174 for pulmonary embolism, 173 Fontan procedure, 82 Food poisoning, 980 Foot care, diabetic, 718, 881, 971-972 Foot ulcers, diabetic, 718, 971-973 osteomyelitis secondary to, 988

Foramen ovale, patent Ebstein anomaly with, 79 migraine headache and, 1095b paradoxical emboli and, 1125 Forced expired volume in 1 second (FEV1), 207-208, 207f in bronchiolitis obliterans, 220 in bronchoprovocation testing, 209, 209f in chronic obstructive pulmonary disease, 216-217 decrease with age, 214-215, 215f decrease with smoking, 214, 215f Forced vital capacity (FVC), 207-208, 207f Formoterol, in chronic obstructive pulmonary disease, 217-218 Foster-Kennedy syndrome, 1099 Fournier gangrene, 973 Fractional excretion of calcium, 773 Fractional excretion of chloride, 299 Fractional excretion of magnesium, 782 Fractional excretion of phosphorus, 780 Fractional excretion of sodium, 299, 300t, 362, 362t in chronic kidney disease, 369 Fractures, in anorexia nervosa, 635-636 Fragile X syndrome, 1120-1121 Frailty, 1198, 1199f palliative care and, 1211 Frameshift mutations, 7 Framingham Study, 16-17, 186, 731 Francisella tularensis, 920 Frank-Starling relationship, 27-28 exercise and, 30-31 heart failure and, 68, 72 FRC. See Functional residual capacity (FRC). Free fatty acids, 643-644, 644f Free water, 309 replacement of, 312 Fremitus, 195, 196t Fresh frozen plasma, 578 Frontal absence seizures, 1144 Frontal lobe epilepsy, 1145 Frontal lobe lesions, 1068-1070, 1069f, 1070t Frontal lobe seizures, 1143-1144, 1143t Frontal lobe tumors, 1155 Frontotemporal dementias, 1074-1075 amyotrophic lateral sclerosis with component of, 1172 Frozen shoulder, in diabetics, 881 Fructosamine, serum, 704 FSH. See Follicle-stimulating hormone (FSH). Fumes, 264-265, 264t Functional residual capacity (FRC), 200-202, 201f measurement of, 207f, 208 Functional status in cancer, 622 in cardiovascular disease, 35-36, 35t in heart failure, 69-70, 69t, 72 preoperative, 275t Fundoscopy, 1098-1099 Fungal infections. See also Aspergillosis; Candida infection. arthritis in, 986-987 of central nervous system, 942-944 cutaneous, 971 in immunocompromised patients, 1032-1033, 1032f of nasal sinuses, 946 Fungal pathogens, 888 laboratory isolation of, 903 potassium hydroxide preparations of, 888, 898 silver staining of, 898 Furosemide. See also Loop diuretics. for hypercalcemia, 618 for hyponatremia, 310-311 mechanism of action, 292-293, 307-308, 308t Furuncles, 969, 970t Fusion complexes, 130, 132 FVC (forced vital capacity), 207-208, 207f G Gabapentin, 1149-1150, 1150t Gadolinium chronic kidney disease and, 371-372 nephrogenic systemic fibrosis caused by, 847, 847t Galactorrhea, 747

Index Gallavardin phenomenon, 43 Gallbladder, 488, 489f Gallbladder cancer, 493-494 Gallbladder disease. See also Cholecystectomy; Cholecystitis. chest pain in, 34t Gallbladder polyps, 494 Gallium nitrate, for hypercalcemia, 618, 618t Gallstone ileus, 491-492 Gallstones, 488-492 acute pancreatitis secondary to, 446, 448, 450, 490-491, 490f, 493 clinical manifestations of, 490-492 differential diagnosis of, 491t inflammatory bowel disease with, 435 management of acute cholecystitis with, 492, 492f natural history of, 490-491, 490f pathogenesis of, 488-490 polyps with, 494 prevalence of, 488 radionuclide studies of, 407, 492 risk factors for, 488, 490t Gangrene Fournier, 973 gas, 974 Gas, subcutaneous, 973-974, 973f Gas exchange, 199, 204, 204f-205f abnormalities of, 204-206, 205f-207f pulmonary anatomy and, 198-199 Gas gangrene, 974 Gases, toxic, 264-265, 264t Gastric. See also Stomach. Gastric biopsy, 421 Gastric bypass, 395, 633-634, 633f, 705 Gastric cancer, 440-441, 440f, 607-608, 607t Helicobacter pylori and, 416-417, 440, 440f, 607 Gastric emptying delayed, 427-428, 427t diabetes and, 703, 718 rapid, 428 reactive hypoglycemia and, 725 Gastric outlet obstruction, 423, 425 Gastric volvulus, 428-429 Gastrin, 415-416, 415f, 419-420 Gastrin-secreting tumors, 426-427 Gastritis, 416-417 autoimmune atrophic, 418 in critically ill patients, 417-419, 418t eosinophilic, 418 Helicobacter pylori and, 416-417, 420f lymphocytic, 418 nonsteroidal anti-inflammatory drugs and, 417 Gastroesophageal reflux disease (GERD), 408-410, 409f, 410t esophageal cancer and, 606 future prospects for, 413b pain in, 34t, 409 in scleroderma, 412, 849 sequelae of, 410 Gastrointestinal bleeding, 385-388 acute, 385-388, 386t, 387f angiography in, 388, 406 chronic, 388 in critically ill patients, 417-419 prophylaxis of, 418, 418t in fulminant hepatic failure, 476-477, 477t in hemolytic uremic syndrome, 587 iron deficiency in, 523 in peptic ulcer disease, 421-422, 423f radionuclide imaging in, 388, 406-407 in ulcerative colitis, 431 variceal, 479-481, 481f beta blockers and, 481, 486, 487b portal vein thrombosis with, 486 Gastrointestinal cancers, 606-609, 607t. See also specific cancers. Gastrointestinal perforation in peptic ulcer disease, 422-423, 425 in ulcerative colitis, 431 Gastrointestinal stromal tumors (GIST), 625, 626t Gastrointestinal tract fluid in, 396 imaging of, 404-407, 405f. See also Endoscopy, gastrointestinal. Gastronoma triangle, 426

Gastroparesis, 427-428, 427t diabetic, 427-428, 718 Gastroscope, 401 GBS. See Guillain-Barré syndrome (GBS). G-CSF. See Granulocyte colony-stimulating factor (G-CSF). Gefitinib, 625-626, 626t Gegenhalten, 1109 Gemcitabine, 623t Gemtuzumab ozogamicin (Mylotarg), 516-517 Gender. See Sex differences. Gene, 2 Gene chips. See DNA microarrays. Gene expression disease phenotype and, 12 DNA microarray studies of, 11, 13, 14b regulation of, 4-6 Gene mapping, 8-9, 10f Gene silencing, 5-6 Gene splicing, 3-4 Gene therapy, 12-13 for muscle diseases, 1190b for Parkinson disease, 1117b Gene-environment interactions, 12 Gene-gene interactions, 12 Generalized tonic-clonic seizure, 1144-1146 in idiopathic epilepsy, 1146 primary, 1146 Generic drugs, 19 Genetic counseling, in epilepsy, 1151 Genetic diseases classification of, 11-12, 11t mitochondrial DNA and, 12 splicing defects and, 3-4 variable expression of, 12 Genetic testing for breast cancer susceptibility, 609-610 for hereditary ataxias, 1117 for hereditary cancer syndromes, 601, 601t for Huntington disease, 1115 for neurologic diseases, 1057, 1057t Genitourinary cancers, 611-614, 611t. See also specific cancers. Genome, 2 GERD. See Gastroesophageal reflux disease (GERD). Geriatric care, 1196, 1206, 1208. See also Older adults. Germ cell tumors, testicular, 766-767 Gerstmann-Sträussler-Scheinker syndrome, 884-885, 1163 Gestational diabetes mellitus, 698-699, 699t follow-up care with, 739 management of, 706 Gestational hypertension, 163 GFR. See Glomerular filtration rate (GFR). GHB (γ-hydroxybutyrate), 1225t-1228t, 1228-1229 Ghon complex, 256 Ghrelin, 631 anorexia nervosa and, 635-636 gastric bypass and, 705 Giant cell arteritis, 169, 859f, 861-862 fever associated with, 922 headache secondary to, 1092 optic neuropathy in, 1099 Giant cell carcinoma, of lung, 267 Giant cell myocarditis, 149 Giardia lamblia infection, 889t, 981t, 982, 984, 1038, 1039t in returning traveler, 1037-1038 Gigantism, 662 Gilbert syndrome, 462-463 GIST (gastrointestinal stromal tumors), 625, 626t Gitelman syndrome, 293-294, 314-316, 315t, 321 Glanzmann thrombasthenia, 572t, 573 Glasgow Coma Score, 1136, 1137t, 1140 Glatiramer acetate, for multiple sclerosis, 1167 Glaucoma, 1099-1100 Gleason sum, 764 Gleevec. See Imatinib (Gleevec). Glimepiride, 710t-713t Glioblastoma multiforme, 1156, 1158b Glioma butterfly, 1155 low-grade, 1157 malignant, 1156, 1158b mixed, 1156

1253

Glipizide, 710t-713t Glitazars, 719b-720b Global aphasia, 1068-1070, 1070t Glomerular basement membrane, 289, 289f autoantibodies against, 237, 327 proteinuria and, 300 Glomerular diseases, 323-332. See also Glomerulonephritis. acute nephritic syndromes, 301-302, 301t, 323-327, 324t. See also Rapidly progressive glomerulonephritis (RPGN). classification of, 323-324, 324t evaluation of, 323f, 324-325, 325f general treatment guidelines for, 325 with glomerular deposition, 323-324, 324t, 330-331 hematuria manifested, 323-324, 324t, 329-330 poststreptococcal, 325 infection-associated, 323-324, 324t, 332 nephrotic. See Nephrotic syndromes. proteinuria in, 300, 325 renal vein thrombosis in, 356 vascular, 323-324, 324t, 331-332 Glomerular filtration rate (GFR), 290-291 assessment of, 298-299, 299t atrial natriuretic peptide and, 306 in chronic kidney disease, 369, 370t, 372 nitrogenous wastes and, 296 prostaglandins and, 305-306 Glomerular tufts, 288, 323 Glomerulonephritis acute kidney injury in, 360f, 363 in Goodpasture syndrome, 237 infective endocarditis with, 962-963 membranoproliferative, 330, 332 membranous, 328-329, 328f, 332 renal vein thrombosis in, 357f pauci-immune, 236, 324-325, 327 poststreptococcal, 324-325, 325t rapidly progressive. See Rapidly progressive glomerulonephritis (RPGN). in Wegener granulomatosis, 236, 327 Glomerulus (renal corpuscle), 286-289, 287f-289f, 323 nitrogenous wastes and, 296 Glossopharyngeal neuralgia, 1093 Glucagon glucose counter-regulation and, 700, 721-722 for hypoglycemia, 726 insulinoma-related, 724 renal degradation of, 297 Glucagon-like peptide-1, 631 β-d-Glucan, assay for, 1031-1032 Glucocorticoid deficiency in adrenal insufficiency, 680-683, 682t in congenital adrenal hyperplasia, 683-684 Glucocorticoid excess, 684, 684t. See also Cushing syndrome. Glucocorticoid therapy. See Corticosteroid therapy. Glucocorticoid-remediable aldosteronism, 178, 321, 688-689 Glucocorticoids, 679, 679f-680f, 681t. See also Cortisol. Gluconeogenesis, 721 in kidney, 297 Glucosamine, for osteoarthritis pain, 872 Glucose, cerebrospinal fluid, infection and, 933, 934t, 935, 940 Glucose, plasma in diabetes, 698, 699t monitoring of, 703-704, 704t, 725 glycemic thresholds and, 722 homeostasis of, 721-722 normal range of, 721 variables affecting, 722 osmolality and, 308 Glucose, renal synthesis of, 297 Glucose counter-regulation, 700, 721-722 Glucose tolerance, impaired, 698, 699t, 703 in metabolic syndrome, 631-632, 700-701 Glucose tolerance test, oral, 698, 699t, 725 for gestational diabetes, 698-699, 699t in suspected neuropathy, 1177-1178 Glucose transporters, renal, 719b-720b Glucose-6-phosphate dehydrogenase, 529, 529f Glucose-6-phosphate dehydrogenase deficiency, 529 α-Glucosidase inhibitors, 710t-713t, 712 Glucotoxicity, 702-703

1254

Index

Glutamate antagonist, for Alzheimer disease symptoms, 1074 γ-Glutamyl transpeptidase, 457, 457t Gluten-sensitive enteropathy. See Celiac disease. Glyburide, 710t-713t Glycemic index, 705 Glycemic thresholds, 721-722 Glycogen storage diseases, hypertrophic cardiomyopathy in, 152 Glycogenolysis, 721 Glycogenoses, 1185-1186, 1186t β2-Glycoprotein I, antibodies against, 585, 587, 841-842, 842t Glycoprotein IIb/IIIa, 555-556, 556f, 557t, 558-560 allotype with coronary risk, 582, 582t autoantibodies directed against, 567-568 fibrinogen and, 575-576 Glanzmann thrombasthenia and, 573 Glycoprotein IIb/IIIa inhibitors, 581-582, 581t in non–ST-segment elevation myocardial infarction, 109-110 in unstable angina, 109-110 Glycosylated hemoglobin. See Hemoglobin(s), glycosylated (HbA1c). GM-CSF. See Granulocyte-macrophage colonystimulating factor (GM-CSF). Goiter, 670, 676-677 in Graves disease, 672-673 in Hashimoto thyroiditis, 674, 676 in subclinical hypothyroidism, 676 toxic multinodular, 674 Gonadotropin-releasing hormone (GnRH), 661t, 666, 691, 692f deficiency of, 692 for male infertility, 694 in women, 732f, 733 Gonadotropins, 660, 666 deficiency of, 662t, 666 in male, 691, 692f for male infertility, 694 Gonadotropin-secreting pituitary tumors, 662t, 666 Gonococcemia, disseminated, 915 Gonorrhea, 1003-1004 arthritis in, 985-986, 986t, 1003 disseminated, 915, 1003-1004 laboratory diagnosis of, 902t, 1003-1004 perihepatitis in, 976, 1003 pharyngeal, 950, 1003 presenting as urinary tract infection, 990-991 screening of adolescent women for, 735 treatment of, 1004 Goodpasture syndrome, 237, 323f, 324-325, 327 Gordon syndrome, 320 Gorlin formula, 60, 89 Goserelin, for prostate cancer, 626-627 Gottron papules, 851 Gout, 819t, 864-869 causes of, 865, 865t chronic polyarticular, 867 clinical presentation of, 865-866 diagnosis of, 866-867, 867f differential diagnosis of, 866 epidemiology of, 864 extra-articular urate deposition in, 867 overview of, 864 pathogenesis of acute arthritis in, 865, 866f in sickle cell disease, 879 treatment of acute, 867-868, 867t intercritical and chronic, 868, 868t uric acid metabolism and, 864-865, 865f Graft-versus-host disease alemtuzumab for reduction of, 943-944 gastric involvement in, 419 vs. scleroderma, 847t in stem cell transplantation, 499-500, 625 Graft-versus-leukemia effect, 500, 513 in chronic lymphocytic leukemia, 548-549 Graft-versus-malignancy effect, 625 Graham Steell murmur, 43-44, 91 Gram stain, 898, 902 of sputum specimen, 954-955, 955t Gram-negative bacteria, 886 Gram-positive bacteria, 886-887 Grand mal seizure, 1144

Granulocyte colony-stimulating factor (G-CSF), 497t, 498-499, 928t with chemotherapy, 627 for neutropenia, 537-538, 1033 in peripheral blood stem cell transplantation, 500, 627 Granulocyte-macrophage colony-stimulating factor (GM-CSF), 497t, 498-499, 535, 928t with chemotherapy, 627 Granulocytes. See also specific granulocyte types. progenitors of, 497-498, 498f Granulocytosis, 535-536 Granuloma inguinale, 999t Granulomatous disorders, hypercalcemia in, 784t, 786 in sarcoidosis, 232-233 Granulomatous thyroiditis, 674 Graves disease, 672-673, 676 thyroid acropachy in, 882 Gray platelet syndrome, 572t, 573 Great arteries, transposition of, 81-82 Growth factors. See Cytokines. Growth hormone, 660-663, 661t-662t deficiency of, 661-662, 662t, 667 future prospects for, 669b glucose counter-regulation and, 700, 721-722 hypersecretion of, 662-663, 662t-663t Growth hormone–releasing hormone, 661t Guidelines, clinical practice, 17 Guillain-Barré syndrome (GBS), 1176-1177, 1177t, 1179-1180 Gummas, 1001 Gynecomastia, 694-696, 695f, 695t H H2 blockers. See Histamine-2 (H2) receptor blockers. HAART (highly active antiretroviral therapy), 1009, 1018t Haemophilus influenzae infection acute meningitis in, 934, 936-937 epiglottitis in, 949 pneumonia in, 255-256, 255t, 956, 959t type b (Hib), vaccines against, 1030 Haemophilus species, 886 Hairy cell leukemia, 549, 878 Haldane effect, 219 Hallucinations, 1081 partial seizures with, 1143-1144 visual, 1096, 1099-1100 in diffuse Lewy body disease, 1113 Hallucinogens, 1225t-1228t, 1231-1232 Hamman crunch, 195 Hampton hump, 172, 242 Hand washing, 1033 Hand-foot syndrome, 879 Hands, herpes simplex virus infection of, 970 Hantavirus, respiratory infection caused by, 954-955 Haploid number, 2 Haplotypes, 7-8, 8f Hashimoto thyroiditis, 674-677 Hashish, 1225t-1228t, 1231 Hastened death, requests for, 1215-1216 HbA1c (glycosylated hemoglobin), 698, 703-704, 704t, 706 hCG. See Human chorionic gonadotropin (hCG). HDL. See High-density lipoprotein (HDL). Head and neck cancers, 606 Head and neck infections, 945-950. See also Pharyngitis. of ear, 945 of epiglottis, 949 of mouth, 946-950, 947t of nose, 945-946 of parapharyngeal soft tissue spaces, 949-950, 949t of sinuses, 945-946 Head injury. See Brain injury, traumatic. Headache, 1086-1093 acute severe, differential diagnosis of, 1088t acute short-lasting syndromes, 1090-1092 in acute sinusitis, 1091 assessment of, 1086, 1087t in emergency room, 1092

Headache (Continued) in brain disease, 1091, 1091t clinical features of, 1088t tumors, 1091, 1091t, 1154-1155 cervicogenic, 1086 classification of, 1086-1092, 1087t cluster headache, 1088-1090, 1095b cranial neuralgias as, 1093 daily chronic, 1091, 1095b new persistent, 1091 fever with, 1091 future prospects for, 1095b in giant cell arteritis, 1092 intracerebral hemorrhage with, 1132, 1133t, 1134 intracranial pressure and, 1091 idiopathic hypertension, 1091-1092 idiopathic hypotension, 1092 migraine. See Migraine. pain-sensitive structures and, 1086 post-traumatic, 1092 in systemic disease, 1092-1093, 1092t tension-type, 1090, 1090t Head-thrust test, of vestibulo-ocular reflex, 1104-1106 Head-up tilt-table testing, 133 Hearing impairments, 1100-1103, 1100f-1101f, 1100t future prospects for, 1103b in older adults, 1203 Heart. See also Cardiac entries. blood supply of, 23-24, 23f to conduction system, 24 cell types in, 25, 25f conduction system of, 24, 24f blood supply to, 24 cells of, 25 ischemic injury to, 98 congenital disease of. See Congenital heart disease. contraction of, 25, 26f. See also Contractility, cardiac. exercise response and, 30-31, 30t gross anatomy of, 22, 23f innervation of, 24-25, 29 muscle physiology of, 25, 26f normal structure and function of, 22-31 trauma to, 157-158, 157t tumors of, 156, 157t Heart failure, 66-74. See also Cardiomyopathy(ies). acute, 66 adaptive mechanisms in, 68-70, 68f-69f aortic coarctation with, 79 aortic stenosis with, 84 causes of, 66, 67t chronic, 66 classification of, 66 defining characteristics of, 66 diastolic, 67 in dilated cardiomyopathy, 151 ejection fraction in, 66-68 diuretics and, 72 preserved, 67-68, 72 resynchronization therapy and, 68 evaluation of, 69-71 high-output, 66 in hypertrophic cardiomyopathy, 153 implantable cardioverter-defibrillators in, 142-143 infective endocarditis with, 961-962, 966 prosthetic valve, 966 low-output, 66 myocardial infarction with, 110-111, 114-115 myocarditis and, 148-149 New York Heart Association functional classification, 69t noncardiac surgery in patient with, 162, 281 in Paget disease of bone, 812 perioperative, 162 in peripartum cardiomyopathy, 164 pleural effusion in, 35, 249 precipitants of, 71-72, 72t in pregnancy aortic stenosis with, 163 mitral stenosis with, 162-163 pulmonary edema in, acute, 67 refractory, 73-74 renal sodium transport in, 295 respiratory control dysfunction in, 246-247 resynchronization therapy for, 68, 73-74

Index Heart failure (Continued) right-sided. See Right heart failure; Right ventricular failure. sex differences in, 745-746 surgical risk and, 274-276, 275t symptoms of, 33, 35 treatment of, 71-73 future prospects for, 74b Heart rate cardiac output and, 27 on electrocardiogram, 46 exercise and, 30-31 myocardial oxygen consumption and, 28-29 Heart sounds. See also Auscultation. abnormal, 40-42, 41t, 42f cardiac cycle and, 27f normal, 39-40 Heartburn, 408-409, 412-413. See also Gastroesophageal reflux disease (GERD). Heat exhaustion, 1083-1084, 1084t Heat shock proteins, 5 Heat stroke, 910-911, 1083-1084, 1084t drug abuse causing, 1084 treatment of, 1084-1085 Heavy-chain disease, 550, 550t, 553 Heerfordt syndrome, 232, 232t Helicobacter pylori, 885 Helicobacter pylori infection diagnostic tests for, 421, 422f dyspepsia and, 384 gastric cancer and, 416-417, 440, 440f, 607 gastritis in, 416-417, 421 hypergastrinemia in, 426-427 iron deficiency in, 523 MALT lymphoma and, 416-417, 440, 542-543 treatment of, 424, 424t in nonulcer dyspepsia, 425-426 ulcers caused by. See Peptic ulcer disease. Heliotrope rash, 851 HELLP syndrome, 184, 351, 368 microangiopathic hemolysis caused by, 528 thrombocytopenia in, 571 Helminthic infections eosinophilia in, 1037 pathogens in, 889 in travelers and immigrants, 1039-1041, 1040t in United States, 1038-1039, 1040t Hemarthrosis, in hemophilia, 879 Hematemesis, 385, 387-388 vs. hemoptysis, 193 Hematin, for porphyria, 656 Hematochezia, 385, 387-388 Hematocrit, normal values for, 497t Hematoma intracerebral, 1132-1133 intramural aortic, 168, 348 Hematopoiesis, 496-498 cytokines and, 496-497, 497t differentiation pathway of, 497-498, 498f extramedullary, 496 in primary myelofibrosis, 510-511 Hematopoietic failure, 498-506. See also Aplastic anemia; Myelodysplastic syndrome. causes of, 499t future prospects for, 506b growth factors for, 499 paroxysmal nocturnal hemoglobinuria in, 502-503 stem cell transplantation for, 499-500 for myelodysplastic syndrome, 504-505 for paroxysmal nocturnal hemoglobinuria, 502-503 Hematuria, 300 benign familial, 330 glomerular diseases manifested as, 323-324, 324t, 329-330 poststreptococcal, 325 Heme, 654, 655f intravenous formulations of, for porphyria, 656 Hemianopia, 1096, 1097f Hemiballism, 1109, 1111t Hemicrania, paroxysmal, 1090 Hemochromatosis, 652-654, 653t arthropathy in, 880 restrictive cardiomyopathy in, 153-154 Hemodialysis. See Dialysis.

Hemodynamic parameters, 26-27, 27f normal values of, 27t Hemoglobin(s) gas exchange and, 204, 205f glycosylated (HbA1c), 698, 703-704, 704t, 706 normal laboratory values for, 497t structure and distribution of, 520, 521t Hemoglobin Barts, 532 Hemoglobin C, 531 Hemoglobinopathies, 529-532. See also Sickle cell disease; Thalassemias. Hemoglobinuria, paroxysmal nocturnal, 502-503, 528-529, 585 Hemolysis hyperphosphatemia secondary to, 791 as prothrombotic state, 585 Hemolytic anemia, 520-522, 521f, 526-532 in antiphospholipid antibody syndrome, 841-842 autoimmune, 522f, 527, 527t differential diagnosis of, 526t in enzyme deficiencies, 529 in erythrocyte membrane abnormalities, 528-529, 528t in hemoglobinopathies, 529-532. See also Sickle cell disease; Thalassemias. immune-mediated, 522f, 527-528, 527t infection-related, 527-528 microangiopathic, 331-332, 332t, 352-357, 526t, 528, 586-587 peripheral blood smear in, 522f peripheral blood smear in, 522f, 527 in Wilson disease, 651 Hemolytic uremic syndrome, 331-332, 332t, 352, 353t, 354-355, 355f, 587 enterohemorrhagic E. coli causing, 981 hemorrhagic colitis in, 587 microangiopathic hemolysis caused by, 528 postpartum, 368 Hemopericardium, 146 Hemophilia, 560, 576 acquired factor inhibitors in, 576-579 articular complications of, 879 factor replacement for, 578, 578t Hemoptysis, 193 bronchiectasis with, 220-221 Hemorrhage. See also Bleeding. intracerebral, 1128, 1132-1133, 1132t-1133t. See also Subarachnoid hemorrhage. pulmonary diffuse alveolar, 235-237 idiopathic, 237 in systemic lupus erythematosus, 835 Hemorrhagic fevers, 917, 1048 Hemosiderosis idiopathic pulmonary, 237 multiple transfusions and, 652 Hemostasis, 555-563. See also Bleeding; Coagulation; Thrombosis. in arterial vs. venous systems, 555, 558 as balance of processes, 555 clot viability and maturation in, 562-563 future prospects for, 563b platelets in. See Platelets. soluble coagulation in, 557f, 560-562 vascular wall in, 555-556, 556f, 556t Henoch-Schönlein purpura, 237, 329-330, 566, 859f, 860 leukocytoclastic vasculitis in, 862 Heparin for acute limb ischemia, 166-167 in antiphospholipid antibody syndrome, 842-843 in cancer patient, hospitalized, 616 for cerebral venous sinus thrombosis, 1131-1132 for deep venous thrombosis, 171 low-molecular-weight vs. unfractionated, 588 in myocardial infarction non–ST-segment elevation, 109-110 with thrombolytic therapy, 112-113 partial thromboplastin time and, 562 perioperative care and, 590 in pregnancy, 590 with prosthetic heart valves noncardiac surgery and, 281 in pregnancy, 163 for pulmonary embolism, 173, 243

1255

Heparin (Continued) stroke and, 1130 thrombocytopenia induced by, 569, 586, 588 in traumatic spinal cord injury, 1139-1140 in unstable angina, 109-110 for venous thromboembolism, 583-584, 587-588, 588t malignancy-associated, 585 for venous thromboembolism prophylaxis, 173-174, 587-588 Heparin resistance, 588 Hepatic. See also Liver entries. Hepatic discriminant function, 471 Hepatic encephalopathy in alcoholic liver disease, 471-472 in cirrhosis, 479, 483-484, 484t in fulminant hepatic failure, 476-477, 477t, 483 in late-onset hepatic failure, 476 Hepatic failure artificial liver support systems for, 487b fulminant, 466, 476-477, 477b, 477t viral, 469-470, 476 hypoglycemia in, 724 inflammatory bowel disease with, 435 late-onset, 476 protein dose in, 639t Hepatic fibrosis in alcoholic hepatitis, 471 new methods for assessing, 459b, 487b Hepatic jaundice, 461t, 462 Hepatic venography, 486 Hepatic venous pressure gradient, 480, 486 Hepatitis, 466-475 acute, 466. See also Hepatitis, viral. anicteric, 468 autoimmune, 474, 475b chronic, 466, 473. See also Hepatitis, viral. defining features of, 466 drug- and toxin-induced, 472-473, 472t genetic, 474-475 granulomatous, 922 Hepatitis, viral acute, 466-470 causative agents of, 466-467, 467f, 467t clinical features of, 468 complications of, 469-470 laboratory findings in, 468 management of, 470 prevention of, 470 serodiagnosis of, 468-469, 468f, 469t-470t transmission of, 467-468, 467t chronic, 470, 473-474, 475b antiviral agents for, 473-474, 475b cirrhosis secondary to, 473-474, 478 hepatocellular carcinoma and, 484-485 liver transplantation for, 485 Hepatitis A infection, 466-470, 467t, 468f, 469t immunization of travelers against, 1034 Hepatitis B infection acute, 466-470, 467f-468f, 467t, 469t-470t arthritis secondary to, 986 chronic, 473-474 glomerular disease in, 332 in HIV-infected patients, 1024-1025 laboratory diagnosis of, 898-899, 899t, 902t polyarteritis nodosa in, 858, 861 Hepatitis C infection acute, 466-470, 467t, 468f, 469t arthritis secondary to, 986 chronic, 474 cryoglobulinemia associated with, 327, 332 in HIV-infected patients, 1024-1025 laboratory diagnosis of, 901, 902t polyarteritis nodosa in, 858, 861 Hepatobiliary scan, 407, 492 Hepatocellular carcinoma, 478-479, 484-485, 485t, 607t, 609 Hepatocellular damage jaundice secondary to, 464 tests of, 456-458, 457t Hepatocytes, 489f Hepatojugular reflux, 36, 70, 216 Hepatopulmonary syndrome, 479, 484-485 Hepatorenal syndrome, 367, 471, 479, 483 Hepcidin, 653

1256

Index

Herbal supplements for benign prostatic hyperplasia, 755 Chinese herb nephropathy and, 335 in chronic kidney disease, 371-372 hepatotoxic, 473 for menopausal symptoms, 744 Hereditary hemorrhagic telangiectasia, 566 Hereditary nephritis, 330 Hereditary neuropathy with liability to pressure palsies, 1174, 1181 Hereditary nonpolyposis colorectal cancer, 441-442, 596, 608 Hermansky-Pudlak syndrome, 572t, 573 HER-2/neu oncogene, 610, 621-622 Heroin, 1225t-1228t, 1229 with cocaine, 1229-1230 heat stroke caused by, 1084 renal failure associated with, 1026 Herpangina, 947 Herpes simplex virus infection encephalitis in, 940 esophagitis in, 413 genital, 998-1000, 999t inguinal lymphadenopathy in, 920 of hands, 970 in HIV-infected patients central nervous system, 1023 cutaneous, 1020t esophageal, 1021, 1021t genital, 1014-1015, 1021 oral, 1021 prophylaxis against, 1019 laboratory diagnosis of, 902t, 1000 meningitis in, 937-938 neonatal, 1000 oral, 946-947 Herpes zoster, 917, 970-971 chest pain in, 34t head pain in, 1093 in HIV-infected patients, 1020t Herpesvirus infection, Tzanck preparation in, 899, 899f Heterophile antibody tests. See Monospot test. Heteroplasmy, 12 Hiatal hernia, gastroesophageal reflux and, 409 Hibernating myocardium, 98 High altitude, hypoxemia at, 206 High-density lipoprotein (HDL), 643-644, 644f, 644t High-density lipoprotein (HDL) cholesterol in coronary artery disease, 97, 102 in diabetes management, 704 dyslipidemia and, 644-646 management of, 646-647, 647t lipid metabolism and, 644 Hill sign, 36 Hippocampal sclerosis, 1145, 1147-1148 Hippus, 1097 His, bundle of, 24, 24f Histamine-2 (H2) receptor blockers for gastroesophageal reflux disease, 410, 410t for peptic ulcer disease, 423-424 for stress bleeding prophylaxis, 418 Histamine-2 (H2) receptors, of gastric parietal cells, 415-416, 415f Histone acetyltransferases, 6 Histone deacetyltransferases, 6 Histones, 5-6, 6f Histoplasma capsulatum infection, 888, 912t, 914-915 disseminated diagnosis of, 1031-1032 in HIV-infected patients, 1024 lymphadenopathy in, 919 meningitis in, 938-939, 942 in HIV-infected patients, 1023 oral lesions in, 947 HIV. See Human immunodeficiency virus (HIV). HLA. See Human leukocyte antigen (HLA) proteins. HMG-CoA reductase, 643-644, 645f HMG-CoA reductase inhibitors. See Statins. Hoarseness, 195 in lung cancer, 267 Hodgkin disease, 546-548 in HIV-infected patients, 1026 staging of, 543-544, 543t, 547-548 Holoprosencephaly, 1120, 1120t

Holter monitoring, 53 in arrhythmias, 132-133 Homans sign, 171, 241-242 Home care, for older adults, 1207 Homocysteine atherothrombosis and, 581, 582t cardiovascular risk and, 97 venous thrombosis and, 582t Homosexual men. See Men who have sex with men (MSM). Hookworm infection, 1039, 1040t Hormonal therapy, for cancer, 626-627 long-term effects of, 619t, 620 Hormone replacement therapy, 743 blood pressure and, 183-184 coronary risk and, 116-117 for gonadotropin deficiency, 666-667 osteoporosis and, 745, 808t, 809 systemic lupus erythematosus and, 839 venous thromboembolism secondary to, 584 Women’s Health Initiative and, 16-17, 731, 743, 809 Horner syndrome, 195, 1097 cluster headache with, 1088-1089 lung cancer with, 267 Hospice, 1215 Hot flashes, 742-743 Housekeeping genes, 5 HPA-1b (human platelet antigen-1b), 582, 582t HPV. See Human papillomavirus (HPV) infection. Human chorionic gonadotropin (hCG) male endocrine function and, 691-693 in testicular cancer, 766 Human Genome Project, 9 Human herpesvirus 6 encephalitis caused by, 943-944, 943t graft-versus-host disease and, 943-944 Human herpesvirus 8. See Kaposi sarcoma. Human immunodeficiency virus (HIV), 884, 1010-1013, 1011f HIV-1 vs. HIV-2, 1008 Human immunodeficiency virus (HIV) infection, 1008-1027. See also Acquired immunodeficiency syndrome (AIDS). acute retroviral syndrome in, 912-913, 919, 1012-1014, 1012f, 1014t initiation of therapy and, 1017 pharyngitis in, 948 adrenal reserve in, 680-681 antiretroviral prophylaxis of, 1026-1027 antiretroviral therapy for change of, 1018-1019 drug regimens in, 1017-1018, 1018t goals of, 1016 hepatitis B co-infection and, 1025 initiation of, 1016-1017, 1016t, 1017f principles of, 1016 cachexia in, 1025 cervical cancer screening in, 742 cervical dysplasia in, 1014-1015, 1021 co-infection with other STIs, 998, 1009 herpes, 1000 syphilis, 939, 1000-1002 constitutional symptoms in, 1020 dementia in, 1021-1022, 1022t, 1075 diagnosis and testing for, 1013 diarrhea in, 1024-1025, 1025t epidemiology of, 1008-1010, 1010f esophageal lesions in, 413, 1021, 1021t fever of unknown origin in, 920-923, 920t, 1025 future prospects for, 1027b gastrointestinal disease in, 1024 hepatitis in, viral, 1024-1025 hepatotoxic agents prescribed for, 472-473 infections in. See also specific infections. AIDS-defining, 1009, 1009t, 1013 antiretroviral therapy and, 1020 CD4 count and, 1014, 1015t, 1019-1020 cutaneous, 1020, 1020t esophageal, 1021, 1021t genital, 1021 nervous system, 1021-1023, 1022t-1023t oral, 1020-1021 prophylaxis against, 1019-1020, 1019t pulmonary, 1023-1024, 1024t tuberculous, 958, 1016, 1023-1024, 1024t

Human immunodeficiency virus (HIV) infection (Continued) initial ambulatory evaluation in, 1015-1016, 1015t lymphadenopathy syndrome in, 856-857 molecular diagnostics in, 900-902, 902t myopathy in, 1026, 1189 nephropathy in, 332, 1026 nervous system complications in, 1021-1023, 1022t-1023t aseptic meningitis, 937, 1014, 1022 cryptococcal meningitis, 938 lymphoma, 1026 subacute meningitis, 938, 1022-1023 Toxoplasma abscesses, 943f occupational exposure to, 1026 pathophysiology of, 1010-1013, 1011f-1012f polyarteritis nodosa in, 861 prevention of, 1026-1027 renal insufficiency in, 1026 rheumatologic complaints in, 1026 spondyloarthropathies, 829-830 sequential manifestations of, 1014-1015 sex-specific manifestations of, 1014-1015 thrombocytopenia in, 568-569 transmission of, 1008-1010 genital ulcers and, 1021 viral load (PVL) in, 1012-1013, 1012f antiretroviral therapy and, 1017-1019 disease progression and, 1017f in early seroconversion, 1013-1014 monitoring interval for, 1016, 1018 Human leukocyte antigen (HLA) proteins, 499-500, 892-897. See also Major histocompatibility complex (MHC) proteins. B27, in spondyloarthropathies, 829, 831 celiac disease and, 394 kidney transplants and, 377, 377f Human papillomavirus (HPV) infection, 999t, 1006 cervical cancer and, 599, 613, 741, 1006 in HIV-infected patients, 1021 penile cancer and, 765 vaccination of girls against, 735, 1006 Human platelet antigen-1b (HPA-1b), 582, 582t Humoral hypercalcemia of malignancy, 784-785 Hungry bone syndrome, 790, 793, 797 Huntington disease, 1115 Hyaluronate, intra-articular, in osteoarthritis, 872 Hydatid disease, 1041 Hydatidiform mole, hyperthyroidism secondary to, 675 Hydralazine lupus caused by, 234 with nitrates, for heart failure, 72 for preeclampsia, 184 Hydrocele, 768-769 Hydrocephalus intracerebral hemorrhage with, 1132-1133 noncommunicating, 1058 normal-pressure, 1075 Hydrocodone, 1214t Hydrocortisone, for adrenal insufficiency, 683 Hydromorphone, 1214t Hydromyelia, 1119-1120 Hydrostatic pressure, 305 Hydroxyapatite, 772-774, 778-779, 782 failure in formation of, 797-798 soft tissue deposition of, 869 Hydroxychloroquine in antiphospholipid antibody syndrome, 842 for rheumatoid arthritis, 827 for systemic lupus erythematosus, 838 11β-Hydroxylase deficiency, 321, 684, 688 17-Hydroxylase deficiency, 178 17α-Hydroxylase deficiency, 688 21-Hydroxylase deficiency, 683-684 Hydroxyurea for essential thrombocythemia, 509-510, 585-586 for leukostasis, 514-515 for polycythemia vera, 509 for primary myelofibrosis, 511 for sickle cell disease, 531 Hyperaldosteronism, secondary, 684t, 688-689. See also Aldosteronism. diabetes secondary to, 700 gradient-limited tubular acidosis with, 320 hypomagnesemia in, 794

Index Hyperaldosteronism, secondary (Continued) metabolic alkalosis with, 321 renal artery stenosis with, 345-346 Hyperbilirubinemia, 457. See also Bilirubin. conjugated, 461t, 463-464 of sepsis, 929 unconjugated, 461t, 462-463 Hypercalcemia, 783-788 in addisonian crisis, 786-787 cancer-associated, 618-619, 618t, 784-785 in breast cancer, 618-619, 786 in lung cancer, 268t, 270 chronic interstitial nephritis with, 334 differential diagnosis of, 784-787, 784t electrocardiography in, 53, 54f familial benign, 786 familial hypocalciuric, 775-776 in granulomatous disorders, 784t, 786 sarcoidosis, 232-233, 786 in hyperparathyroidism, 785-786 in hyperproteinemia, 787 in hyperthyroidism, 786 hypomagnesemia secondary to, 794 in immobilization, 787 in liver disease, end-stage, 787 local osteolytic, 785 in manganese intoxication, 787 medications causing, 786 in milk-alkali syndrome, 786-787 in Paget disease of bone, 814 in parenteral nutrition, 787 pathophysiology of, 784 with pheochromocytoma, 786 renal failure with, 783, 785-787 symptoms and signs of, 783-784 treatment of, 787-788 with VIPoma, 786 Hypercalciuria, 342 in Bartter syndrome, 316 congenital, 291 in Gordon syndrome, 320 in gradient-limited renal tubular acidosis, 320 in hyperparathyroidism, 785 renal calculi and, 342-343, 342t in sarcoidosis, 232 Hypercapnia, severe, 321-322 Hyperchloremic metabolic acidosis in chronic kidney disease, 369 gradient-limited tubular, 320 urinary anion gap in, 299-300 Hypercholesterolemia. See also Dyslipidemia. familial, 648 in hypothyroidism, 676 polygenic, 649 Hypercoagulable states. See Thrombosis. Hypergastrinemia, 426-427 Hyperglycemia in diabetes mellitus, 702-703 parenteral nutrition and, 641 seizures caused by, 1151 in sepsis syndrome, 929 stress-induced, 706-707 Hyperglycemic crises, 715-716, 715t Hyperglycemic hyperosmolar state, 715t, 716 Hyperhomocysteinemia. See Homocysteine. Hyperinsulinemia β-cell tumor causing, 724 in metabolic syndrome, 700-701 in type 2 diabetes, 702-703 Hyperkalemia, 312-313, 313f in acute kidney injury, 364 in chronic kidney disease, 375 electrocardiography in, 53, 54f, 364 renal tubular acidosis with, 319t, 320-322 Hyperkalemic hypertension, familial, 320 Hyperkalemic periodic paralysis, 1186t, 1187-1188 Hyperleukocytosis syndrome, 514-515 Hyperlipidemia. See Dyslipidemia. Hyperlipoproteinemia, familial combined, 649 Hypermagnesemia, 793, 793t hypocalcemia associated with, 790 Hypermetria, 1111t Hypermotor seizures, 1144 Hypernatremia, 311-312, 311f Hyperosmolar nonketotic syndrome, 715t, 716

Hyperostosis, diffuse idiopathic skeletal, 881 Hyperoxaluria, 342-343, 342t chronic interstitial nephritis with, 334 Hyperparathyroidism, 785-786 bone disease in, 795-797, 796f-797f, 800 in chronic kidney disease, 373-376, 374f cinacalet for, 796-799 hypophosphatemia in, 792 musculoskeletal manifestations of, 881t, 882 neonatal severe, 786 renal osteodystrophy in, 798-799 renal tubular acidosis and, 320 Hyperphosphatemia, 791-792, 791t in chronic kidney disease, 375-376 hypocalcemia secondary to, 788t, 790 Hyperprolactinemia, male hypogonadism secondary to, 692 Hyperreactive airways disease, bronchoprovocation testing in, 209, 209f Hyperreflexia, 1108-1109 Hypersensitive sites, 6 Hypersensitivity myocarditis, 149 Hypersensitivity pneumonitis, 197, 225-227, 227f, 228t-229t, 231, 238, 238t drug-induced, 234 Hypersomnia syndromes, 1066 Hypertension, 174-186 acute severe, 184-185, 185t in African Americans, 180 renal disease and, 175, 331, 350 in women, 746 cardiovascular risk in, 174, 175f cerebral blood flow and, 1124-1125, 1124f in chronic kidney disease, 182, 184, 350, 370 coronary artery disease and, 97 in diabetes mellitus, 182, 706, 719 with chronic kidney disease, 370-371 epidemiology of, 174, 174f future prospects for, 186b in glomerular diseases, 325 in high-risk patients, 180 initial evaluation for, 174 risk stratification in, 175-176, 176t secondary hypertension and, 176-178, 177t, 178f staging in, 174-175, 175t, 176f intracerebral hemorrhage in, 1132 isolated systolic, in older adults, 182-183, 183f lacunar stroke associated with, 1126 with left ventricular hypertrophy, 186 masked, 175, 176f metabolic syndrome and, 631-632, 700-701 oral contraceptives and, 183-184 peripheral arterial disease with, 166 in polycystic kidney disease autosomal dominant, 338 autosomal recessive, 338-339 in pregnancy, 163, 184, 351-352, 352t follow-up care with, 739 with thrombocytopenia, 571 prognosis with, 186 pseudoresistant, 184 rare inherited forms of, 178 renal parenchymal, 177, 177t renal transport processes and, 296 renovascular, 177, 177t, 345-352. See also Renal artery stenosis. resistant, 184 in scleroderma renal crisis, 846 secondary causes of, 176-178, 177t, 178f, 184 hyperaldosteronism, 688-689 pheochromocytoma, 689 sleep apnea with, 245-246 in stroke, acute, 1131 stroke risk in, 174, 175f subarachnoid hemorrhage and, 1134 in Takayasu arteritis, 861 treatment of, 179. See also Antihypertensive agents. with lifestyle modifications, 179 lifetime benefit of, 186 after stroke, 183-185, 1132 uncomplicated, 179-180 in women, 746 Hypertensive emergencies, 184-185, 185t aortic dissection as, 350 Hypertensive encephalopathy, 184-185, 1131

1257

Hypertensive nephrosclerosis, 182, 331, 336, 350-351 Hypertensive retinopathy, 184-185, 184f Hypertensive urgencies, 184-185 Hyperthermia, 910, 1083-1085, 1084t malignant, 1084, 1186t, 1188 Hyperthyroidism, 672-674 apathetic, 673, 882 differential diagnosis of, 672, 672f, 672t factitious, 674 goiter in, 674, 676 in Graves disease, 672-673, 676 hypercalcemia in, 786 musculoskeletal manifestations of, 881t, 882 rare causes of, 674-675 signs and symptoms of, 672, 672t subclinical, 674 in thyroiditis, 674 thyrotropin-secreting pituitary tumors with, 664 with toxic adenoma, 673-674 with toxic multinodular goiter, 674 Hypertriglyceridemia, familial, 650. See also Triglycerides. Hypertrophic cardiomyopathy, 149, 150t, 151-153 bisferious pulse in, 36-38, 38f echocardiography in, 71f magnetic resonance imaging in, 60-61, 62f noncardiac surgery in patient with, 281-282 surgical myectomy for, 152, 153f Hypertrophic osteoarthropathy, 878 Hypertrophic pulmonary osteoarthropathy, 194-195, 268t Hyperuricemia. See also Gout. acute kidney injury secondary to, 367 asymptomatic, 868-869 causes of, 865, 865t chronic interstitial nephritis with, 334 in metabolic syndrome, 700-701 in sickle cell disease, 879 Hyperuricosuria, 342t, 343 in sickle cell disease, 879 Hyperventilation absence seizures triggered by, 1147 central, 246 for elevated intracranial pressure, 1137-1138 respiratory alkalosis caused by, 322 symptoms associated with, 1148 Hyperviscosity syndrome Eisenmenger syndrome with, 82 Waldenström macroglobulinemia with, 552-553 Hypnic headache, 1090-1091 Hypnotic agents, 1064, 1066, 1066t in sleep disorders, 1066, 1066t Hypoaldosteronism, 683. See also Pseudohypoaldosteronism. hyporeninemic, 312-313, 320, 683 Hypocalcemia, 788-791 in acute tubular necrosis, 364 in chronic kidney disease, 374, 374f differential diagnosis of, 788-791, 788t electrocardiography in, 53, 54f in hypermagnesemia, 790 in hyperphosphatemia, 788t, 790 in hypoalbuminemia, 790 in hypomagnesemia, 790 in hypoparathyroidism, 788t, 789 medications causing, 788t, 790 in pancreatitis, 790-791 acute, 447-448 pathophysiology of, 788 in pseudohypoparathyroidism, 788t, 789 in rapid bone formation, 788t, 790 in sepsis, 790 symptoms and signs of, 788 in vitamin D disorders, 788t, 789-790 Hypocalciuria in familial hypocalciuric hypercalcemia, 775-776 in Gitelman syndrome, 316 Hypochondriasis, 1081-1082 Hypocitraturia, 342, 342t Hypocretin, 1066 Hypogammaglobulinemia, bronchiectasis in, 220-221 Hypoglycemia, 721-727 alimentary, 725-727 artifactual, 726 after bariatric surgery, 634

1258

Index

Hypoglycemia (Continued) cerebral effects of, 722, 722t clinical classification of, 722-725, 723t definition of, 721 diagnostic work-up of, 725-726, 726t factitious, 723, 726 fasting, 723-725, 723t in fulminant hepatic failure, 476, 477t future prospects for, 727b glycemic threshold for symptoms of, 722 idiopathic, 725 reactive (postprandial), 723t, 725 in sepsis syndrome, 929 signs and symptoms of, 721-722, 722t treatment of, 726-727 juice for, 704-705, 726 Hypoglycemic agents. See Antidiabetic agents. Hypogonadism central, 666 female hypergonadotropic, 735-736 hypothalamic, 736 male, 691-694, 692t, 694f erectile dysfunction in, 760 Hypokalemia, 312-314, 314f in chronic kidney disease, 375 electrocardiography in, 53, 54f, 313 in gradient-limited renal tubular acidosis, 320 hypomagnesemia caused by, 794 in primary aldosteronism, 177-178, 688 Hypokalemic periodic paralysis, 1186t, 1188 Hypomagnesemia, 793-794, 793t in Gitelman syndrome, 316 hypocalcemia in, 790 hypokalemia with, 314 Hypomania, 1080 Hypometria, 1111t Hyponatremia, 309-311, 310f in cirrhotic ascites, 482 in heart failure, 70, 72 in lung cancer, 268t, 270 Hypoparathyroidism, 788t, 789 hyperphosphatemia secondary to, 791-792 musculoskeletal manifestations of, 881t Hypophosphatasia, 799-800 Hypophosphatemia, 792-793, 792t osteomalacia and rickets in, 798 X-linked, 792-793 Hypopituitarism, 667, 667t Hypopnea, definition of, 245 Hyporeninemic hypoaldosteronism, 312-313, 320, 683 Hypospadias, 693 Hypotension orthostatic. See Orthostatic hypotension. in sepsis syndrome, 929 Hypothalamic dysfunction, 667, 692 Hypothalamic hormones, 660, 661f, 661t Hypothalamic-pituitary axis, 660-669, 661f, 661t Hypothalamic-pituitary-adrenal axis, 679, 681f Hypothalamic-pituitary-gonadal axis, 666 male, 691-694, 692f, 692t Hypothalamic-pituitary-thyroid axis, 670, 671f Hypothermia, 1083, 1084t as neuroprotective therapy, 1085b perioperative cardiac events and, 280 in sepsis syndrome, 928-929 Hypothyroidism, 675-676 causes of, 675, 675t clinical manifestations of, 675, 675t differential diagnosis of, 676 goiter in, 676 hyperlipidemia in, 648t, 649-650 hypoglycemia in, 724 laboratory tests in, 675-676 musculoskeletal manifestations of, 881-882, 881t postpartum thyroiditis and, 739-740 subclinical, 676 in thyroiditis, 674 Hashimoto, 674, 676 thyroid-stimulating hormone in, 664 treatment of, 676 Hypotonia, 1111t, 1116 Hypoventilation, 205 in chest wall disease, 251

Hypovolemia, 306-307, 307t hypercalcemia in, 787 hypernatremia associated with, 311-312, 311f Hypovolemic shock, 262, 263t Hypoxemia causes of, 204-206, 205f-207f definition of, 204-205 in lung disorders, 188 ventilatory response to, 202-203, 203f Hypoxia cerebral, 1125 definition of, 204-205 in lung disorders, 188 I IABP. See Intra-aortic balloon pump (IABP). Ibandronate, for osteoporosis prevention and treatment, 807-808, 808t Ibritumomab tiuxetan, for follicular lymphomas, 544 Ibutilide, 137t-138t, 139 ICDs. See Implantable cardioverter-defibrillators (ICDs). ICF (intracellular fluid), 305, 306f Ictal phase, 1142-1143 Icterus. See Jaundice. Ictus, 1142-1143 ICU. See Intensive care unit (ICU). IDL. See Intermediate-density lipoprotein (IDL). IGF-I (insulin-like growth factor I), 661-663 IGF-II (insulin-like growth factor II), from rare tumors, 725, 726t Ileal conduit, 612 Ileitis, backwash, 435-436 Ileum, endoscopy of, 402 Iloprost, in Buerger disease, 169 Imatinib (Gleevec), 13, 512-513, 518, 518b, 595, 625, 626f, 626t Imiquimod, 1006 Immobilization, hypercalcemia secondary to, 787 Immotile cilia syndrome, 214t Immune response modifiers, central nervous system infections and, 942-944, 943t Immune system. See Infections, host defenses against. Immune thrombocytopenic purpura (ITP), 568-569 maternal, 570 Immunizations. See also Vaccines. for adolescent females, 735 recommended for women, 734t conception and, 737 for travelers, 1034-1035 against varicella-zoster virus, 970 Immunocompromised host, 1028-1033. See also Immunosuppressant drugs. cell-mediated immunity and, 1028-1029, 1029t diagnostic problems in disseminated mycoses, 1031-1032, 1032f pulmonary infiltrates, 1031, 1032f future prospects for, 1033b humoral immunity and, 1029-1030 immunosuppressive therapy and, 863 neutropenia and, 1030-1033, 1031t neutrophil dysfunction and, 1030 strongyloidosis in, 1039 Immunodeficiency, congenital, 1028, 1029t Immunofluorescence techniques, 898-899, 899t, 900f Immunoglobulin(s). See also Antibodies. glomerular deposition of, 323f, 324-325, 327, 330-331 IgA-associated disorders Henoch-Schönlein purpura, 566, 860 IgA nephropathy, 329-330, 566 in immune hemolytic anemia, 527-528 intravenous. See Intravenous immunoglobulin. in liver disease, 456 monoclonal glomerular deposition of, 330-331 in plasma cell disorders, 550-554, 550t RhoGAM, for immune thrombocytopenic purpura, 569

Immunosuppressant drugs. See also Immunocompromised host. adverse effects of, 863 for kidney transplantation, 377-378 mechanisms of action, 377-378, 378f Impaired fasting glucose, 698, 699t Impaired glucose tolerance, 698, 699t, 703 Impetigo, 969-970, 970t glomerulonephritis secondary to, 325, 969-970 Implantable cardioverter-defibrillators (ICDs), 142-143 in arrhythmia syndromes, 143-144 in dilated cardiomyopathy, 151 future prospects for, 144b in hypertrophic cardiomyopathy, 153 Impotence, 759. See also Erectile dysfunction. Incisional tachycardia, 124-125 Inclusion body myositis, 850-853, 852f, 1188-1189, 1189t Incretin mimetics, 710t-713t, 714 India ink preparation, 898, 899f, 938-939 Indicator dilution measurement, of cardiac output, 59-60 Indomethacin, for cluster headache, 1090 Infant respiratory distress syndrome, 189 Infantile spasms, 1146-1147 Infection control, 992 Infections. See also specific infections and sites. definition of, 925, 926t esophageal, 413 febrile. See Fever. gastric, 419. See also Helicobacter pylori infection. glomerular diseases associated with, 323-324, 324t, 332 health care–associated, 992-997 approach to patient with, 992-993, 993t catheter-associated, intravascular, 995, 997t catheter-associated, urinary tract, 993, 993t Clostridium difficile in, 995 definition of, 992 epidemiology of, 992 infection control and, 992 pathogens in, 992 pulmonary, 255-256, 255t, 956, 994-995, 994f risk factors for, 992 surgical site, 997 host defenses against, 890-897 categories of, 891-893 cellular interactions and, 893 diversity of recognition in, 893-894, 894f, 896 host-microbe interaction in, 894-896, 895f microbial evolution and, 890-891 microbial pathogenesis and, 890, 896-897 immunosuppression and. See Immunocompromised host. in kidney transplant recipients, 378, 379f laboratory diagnosis of, 898-903 by cytologic examination, 899, 899f by direct visualization, 898, 899f by histopathologic examination, 899 by isolation in culture, 902-903 by microbial antigens, 898-899, 899t, 900f by molecular techniques, 900-902, 901f, 902t lymph node enlargement in, 541t, 553-554 lymphocytosis in, 553-554 pathogens causing, 884-889, 889t travel and. See Diarrhea, traveler’s; Traveler’s infections. Infective endocarditis, 961-966 antibiotic prophylaxis of, 967, 967t atrial septal defect and, 77 bicuspid aortic valve and, 78 indications for, 93-94, 94t, 967, 967t mitral stenosis and, 89 mitral valve prolapse and, 90-91 regimens for, 967, 967t aortic coarctation complicated by, 79 with aortic stenosis, congenital, 78 blood cultures in, 921 causative organisms in, 963, 964t antibiotics suggested for, 965-966, 965t nonendocarditis bacteremia and, 963, 965t syndromes associated with, 965t clinical features of, 962, 962t diagnostic criteria for, 963, 964t differential diagnosis of, 963

Index Infective endocarditis (Continued) embolization in, 962-963, 966-967, 1162 endarteritis secondary to, 967 epidemiology of, 961 fungal, 966 in intravenous drug users, 961-962 microorganisms in, 964t-965t Pseudomonas in, 966 surgery for, 966 laboratory findings in, 962-963 management of, 963-966 antibiotics in, 963-966, 965t surgery in, 966 mycotic aneurysms secondary to, 962, 967, 1133 neurologic complications of, 962, 1162-1163 outcome of, 963 pathogenesis of, 961-962 prosthetic valve, 961, 966 microorganisms in, 964t prophylaxis of, 93-94 ventricular septal defect and, 77 warfarin contraindicated in, 1128-1130 Inferior petrosal sinus sampling, 687 Infertility female, 741 in anorexia nervosa, 636 male, 693-694, 741 varicocele and, 768 Inflammation. See also Systemic inflammatory response syndrome. in atherosclerosis, 95, 97 in diabetes mellitus, 703 fever associated with, 95 Inflammatory arthritis. See also Arthritis. clinical presentation of, 818 synovial fluid analysis in, 820, 821t Inflammatory bowel disease, 430-438. See also Crohn disease; Ulcerative colitis. arthritis associated with, 434, 829-833, 830t causes of, 430-431 clinical features of in Crohn disease, 432 in ulcerative colitis, 431-432 diagnosis of, 433, 433f-434f differential diagnosis of, 433-434 epidemiology of, 430 extraintestinal manifestations of, 434-435, 435t treatment of, 436-438, 436t antibiotic therapy in, 436 video capsule endoscopy in, 402 Infliximab, 13 alcoholic liver disease and, 471-472 central nervous system infections and, 942-944, 943t for inflammatory bowel disease, 437 for rheumatoid arthritis, 827, 827t for spondyloarthropathies, 832 Influenza, 912, 912t, 955 acute myositis in, 1189 antiviral agents for, 955, 1036 avian, 913, 955, 1036-1037 pandemics of, 258b in returning traveler, 1037 Influenza vaccine, 960, 960t for travelers, 1035 Inguinal lymphadenopathy, 920 Inhalant abuse, 1225t-1228t, 1232 Inhalation injuries, 264-265, 264t Inhibin, 666, 691, 742 Inotropic agents, for heart failure, 72-73 after myocardial infarction, 114-115 refractory, 73-74 Inotropy. See Contractility, cardiac. INR (international normalized ratio), 561-562 Insomnia, 1064 circadian rhythm and, 1066 familial fatal, 884-885, 1163 Insulin autoantibodies to, 725 combined with noninsulin agents, 708 pramlintide, 714 thiazolidinediones, 713 dosing of, 707-708 hypoglycemia caused by in diabetics, 723 in hospitalized patients, 724

Insulin (Continued) inhaled preparation, 719b-720b injection sites and technique, 708 intensive therapy with, 707 parenteral nutrition and, 641-642 preparations of, 707-708, 709t renal degradation of, 297 for septic patients, 930 standard therapy with, 707 in type 2 diabetes, 708 Insulin infusion pump, 706-707, 719 dose calculation for, 707 Insulin resistance. See also Metabolic syndrome. in chronic kidney disease, 374 counter-regulatory hormones and, 700 genetic states with, 700 nonalcoholic steatohepatitis and, 474 in type 2 diabetes, 699, 702-703 uric acid stones and, 343 Insulin sensitizers, 712-713 Insulin tolerance test, 661, 662t, 664 Insulin-induced hypoglycemia test. See Insulin tolerance test. Insulin-like growth factor I (IGF-I), 661-663 Insulin-like growth factor II (IGF-II), from rare tumors, 725, 726t Insulinoma, 724-726, 726t Integrated volume response, 305-306, 306f Integrative (secondary) research studies, 17, 17t Intensive care unit (ICU). See also Critical care medicine. acute quadriplegic myopathy in, 1190 calorie requirement in, 639 fever of unknown origin in, 923 hypomagnesemia in, 793-794 hypophosphatemia in, 792 parenteral nutrition in, 640-641 pneumonia admitted to, 953-954, 954t, 958t traumatic spinal cord injury in, 1139 Intention tremor, 1111t, 1116 Intention-to-treat analysis, 18 Interatrial septum, lipomatous hypertrophy of, 156 Interferon(s) in cancer therapy, 627 functions of, 893, 897 Interferon-α, 893 for essential thrombocythemia, 509-510 for hepatitis B, 473-474 for hepatitis C, 470, 474 for polycythemia vera, 509 for primary myelofibrosis, 511 Interferon-β, 893 for multiple sclerosis, 1167 Interferon-γ, 893, 928t Interictal phase, 1142-1143 Interleukin(s), in systemic inflammation, 928t Interleukin-2 for metastatic melanoma, 614, 627 for renal cell carcinoma, 612, 627 Intermediate-density lipoprotein (IDL), 643-644, 644f, 644t Intermittent claudication. See Claudication. International normalized ratio (INR), 561-562 Internet, medical information sources, 18-19, 19t Interstitial cystitis, 747 Interstitial fluid, 305, 306f Interstitial lung diseases, 190-191, 190f, 225-240 biopsy in, 226-227, 228t-229t classification of, 225 connective tissue disorders and, 225-226, 231, 233-234, 234t diagnostic testing in, 226, 228t-229t diffuse alveolar hemorrhage in, 235-237 drug-induced, 225-227, 228t-229t, 231, 234-235, 235t in connective tissue disorders, 233 environmental or occupational exposures and, 225-226, 237-238. See also Hypersensitivity pneumonitis; Pneumoconioses. eosinophilic, 239-240 epidemiologic background in, 225 future prospects for, 240b granulomatous, 231-233. See also specific diseases. history in, 225

1259

Interstitial lung diseases (Continued) idiopathic pneumonias, 227-231, 227f, 228t-229t, 230f. See also specific pneumonias. imaging in, 210, 225-227, 227f, 228t-229t interstitium of lung and, 226, 227f Langerhans cell histiocytosis, 225, 228t-229t, 238-239 lymphangioleiomyomatosis, 226, 228t-229t, 239 management of, 227 physical examination in, 226, 228t-229t in polymyositis/dermatomyositis, 850-851 presentation of, 225 with preserved lung volumes, 226, 227f pulmonary alveolar proteinosis, 240 rheumatoid arthritis with, 825-826 in systemic sclerosis, 845, 846t, 847-848, 848t typical manifestations of, 228t-229t vasculitic, 235-237 Interstitial nephritis acute, 302, 333, 334t, 361 chronic, 333-336 causes of, 334-336, 335t clinical presentation of, 334, 334t Interstitial pneumonias acute, 227-231 idiopathic, 227-231, 227f, 228t-229t, 230f. See also specific pneumonias. nonspecific, 227-231, 233-234 Intervertebral disks, herniation of, 1093-1095 Intestinal dysmotility diarrhea secondary to, 397t, 398 in systemic sclerosis, 849 Intestinal obstruction, in Crohn disease, 432 Intimate partner violence, 747-748, 748t Intra-aortic balloon pump (IABP), 73-74 aortic regurgitation and, 87 in cardiogenic shock, 115 for papillary muscle rupture, 116 for ventricular septal defect, postinfarction, 116 Intracellular fluid (ICF), 305, 306f Intracerebral hemorrhage, 1128, 1132-1133, 1132t-1133t. See also Subarachnoid hemorrhage. Intracranial hypertension with brain tumors, acute treatment of, 1156 idiopathic cerebral venous sinuses and, 1103b, 1162 headache caused by, 1091-1092 visual loss caused by, 1099 optic nerve atrophy with, 1099 in traumatic brain injury, 1136-1137 Intracranial hypotension, headache caused by, 1092 Intracranial pressure. See also Intracranial hypertension; Intracranial hypotension. in fulminant hepatic failure, 476 monitoring of, in traumatic brain injury, 1136, 1138 Intrapleural pressure, 200, 201f, 202 Intravenous cannulas, suppurative phlebitis secondary to, 968 Intravenous immunoglobulin for alloimmune thrombocytopenia, 569-570 for dermatomyositis, 853-854 for drug-induced immune thrombocytopenia, 569 for Guillain-Barré syndrome, 1179-1180 for immune thrombocytopenic purpura, 568-569 for Kawasaki disease, 861 for myasthenia gravis, 1192 for systemic lupus erythematosus, 838 Intravenous pyelography, 303 Intrinsic factor, 415-416, 524-525 Introns, 3, 3f genetic diseases associated with, 12 Intubation, endotracheal, 260. See also Mechanical ventilation. complications of, 261-262 in epiglottitis, 949 in Guillain-Barré syndrome, 1179 infection control with, 994-995 in Ludwig angina, 950 pneumonia secondary to, 255 in traumatic brain injury, 1136 in traumatic spinal cord injury, 1138-1139 Ion channelopathies. See Channelopathies. Ipratropium bromide, in chronic obstructive pulmonary disease, 217-218 Irinotecan, 623t, 625 Iritis, inflammatory bowel disease with, 435

1260

Index

Iron. See also Hemochromatosis. anemia of chronic disease and, 526 metabolism of, 652-653 normal indices of, 653t overdose of, 264t Iron deficiency anemia, 522-523, 522f esophageal webs and, 412 restless legs syndrome caused by, 1067 in systemic sclerosis, 849 Iron supplementation, in chronic renal failure, 526 Irritable bowel syndrome, 384-385, 747, 876 Ischemic heart disease. See also Coronary artery disease (CAD); Myocardial ischemia. cardiomyopathy secondary to, 66 surgical risk and, 274-276, 275t Ischemic penumbra, 1125 Islet cell transplantation, 719b-720b, 727b Islet cell tumors β-cell, 724 secreting vasoactive intestinal polypeptide, 786 Isoniazid, hepatotoxicity of, 472-473 Isospora belli infection, 889t, 982, 984 in HIV-infected patients, 1024-1025, 1025t ITP (immune thrombocytopenic purpura), 568-569 maternal, 570 IVC filter. See Vena caval filter. J J point, 47 Jaccoud arthropathy, 835 Jacksonian march, 1143-1144 Janeway lesions, 962t Janus kinase 2 (Jak-2) mutations, in myeloproliferative disorders, 507, 518b, 585-586 essential thrombocythemia, 509 polycythemia vera, 508-509 Jarisch-Herxheimer reaction, 1002 Jaundice, 460-465. See also Hyperbilirubinemia. in acute viral hepatitis, 468, 468f classification of, 460, 461t clinical approach to, 464, 464f in conjugated hyperbilirubinemia, 461t, 463-464 definition of, 460 future prospects for, 464b neonatal, 460, 463, 463t postoperative, 463 in unconjugated hyperbilirubinemia, 461t, 462-463 JC virus. See Progressive multifocal leukoencephalopathy. Jejunum digestion in, 390 endoscopy of, 402 lipid absorption in, 389 Jervell and Lange-Nielsen syndrome, 142-143 Joint replacement surgery for osteoarthritis, 872 for rheumatoid arthritis, 827 Jones criteria, modified, 92, 92t J-point elevation, 51-53 Jugular vein, thrombophlebitis of, septic, 949, 949t Jugular venous pulse, 27f, 36, 37f Junctional complexes, of proximal tubule, 291 Junctional premature complexes, 121, 121f Junctional tachyarrhythmias, 127-129, 128f Juvenile absence epilepsy, 1146 Juvenile myoclonic epilepsy, 1144, 1146, 1149-1150 Juvenile nephronophthisis, 339 Juxtaglomerular apparatus, 288f, 289, 297 K Kallmann syndrome, 692 Kaposi sarcoma, 1026 herpesvirus causing, non-Hodgkin lymphoma and, 542-543 oral lesions in, 1021 pulmonary, 1024t Kartagener syndrome, bronchiectasis in, 220 Kawasaki disease, 97-98, 859f, 861 Kayser-Fleischer rings, 1114-1115 Kearns-Sayre syndrome, 1187 Kennedy disease, 1173-1174

Keratinocyte growth factor, recombinant, 627 Keratoconjunctivitis sicca diagnosis of, 856 differential diagnosis of, 856-857 in Sjögren syndrome, 855-856, 856t treatment of, 857, 857t in systemic lupus erythematosus, 835 Keratoderma blennorrhagicum, 831 Kerley B lines, 46 Kernicterus, 460, 463, 463t Ketamine, 1225t-1228t, 1231-1232 Ketoacidosis, 318-319 diabetic, 698, 715-716, 715t Ketogenic diet, 1150 Kidney(s). See also Renal entries. abscess of, 922, 962 acid-base balance and, 294-295, 316-319, 317f blood flow in, 290 functions of, 290, 290t, 296-297. See also Distal nephron; Proximal tubule. future prospects for, 297b, 304b infection of, 989-991 structure of, 286-290 blood supply, 286, 287f, 345, 346f glomerulus (corpuscle), 286-289, 287f-289f, 323 gross anatomy, 286, 287f innervation, 286 nephron, 286-288, 287f tubules, 286-290, 287f-288f tuberculosis involving, 991 volume homeostasis and, 305-306, 306f. See also Volume disorders. Kidney disease. See also Acute kidney injury (AKI); Chronic kidney disease (CKD); Glomerular diseases; Interstitial nephritis. assessment of, 298-301. See also Renal biopsy; Urinalysis. history in, 298 imaging in, 302-303, 303t. See also specific modalities. physical examination in, 298 renal function tests in, 298-300, 299t-300t cystic, 336-337, 337t future prospects for, 304b major syndromes in, 301-302, 301t Kidney stones. See Nephrolithiasis. Kidney transplantation, 376-379 acquired cystic kidney disease and, 339 complications of, 378-379, 379f deceased vs. living donors for, 377, 377t in diabetic patient, 717 HLA matching for, 377, 377f immunosuppressant drugs for, 376-378 Killip classification of myocardial infarction, 114-115 c-KIT, anticancer agents targeting, 625, 626t Klatskin tumor, 493-494, 494f Klebsiella, 886 Klinefelter syndrome, 692-693 Knockout animal, 10 KOH (potassium hydroxide) preparation, 888, 898 Korotkoff sounds, 36 Korsakoff syndrome, 1071, 1076, 1224 Kostmann syndrome, 536-537 Kussmaul sign, 36 in constrictive pericarditis, 147 in right ventricular infarction, 115 Kyphoplasty, 809-810 Kyphoscoliosis, 251-252 L Labetalol, for hypertensive crisis, 185, 185t Labyrinthitis, 1102 Lacosamide, 1149-1150, 1150t Lactate, serum, in sepsis, 929 Lactate dehydrogenase (LDH) in pleural fluid, 249-250, 249t serum, in testicular cancer, 766 Lactation. See Breastfeeding. Lactic acidosis, 318-319 mitochondrial encephalomyopathy with, 1187 Lactose intolerance, 393-394 Lactulose, for hepatic encephalopathy, 476, 483-484 Lacunar stroke, 1126

Lambert-Eaton myasthenic syndrome, 268t, 270, 619t, 1192-1193 Laminar necrosis, 1125 Lamotrigine, 1149-1150, 1150t in pregnancy, 1152 Langerhans cell histiocytosis, pulmonary, 225, 228t-229t, 238-239 Lansoprazole for peptic ulcer disease, 423-424 for stress bleeding prophylaxis, 418 Laplace’s law, wall stress and, 28 Large cell tumors, of lung, 266-267, 603 Large granular lymphocyte leukemia, 537 Large granular lymphocytes, 540-541, 893 Large-scale biology, 9 Laryngeal cancers, 606 Laser revascularization, transmyocardial, 105 Lateral frontal seizures, 1144 Lateral sinus thrombosis, septic, 1162 Laxative abuse, 314 LDH. See Lactate dehydrogenase (LDH). LDL. See Low-density lipoprotein (LDL). Lead nephropathy, 335 Lead poisoning, anemia in, 522-523 Lead-time bias, 600-601 Leber hereditary optic neuropathy, 1099 Leflunomide, for rheumatoid arthritis, 827 Left atrial hypertrophy, electrocardiography in, 50, 50t Left dominant circulation, 23-24 Left ventricular diastolic pressure, heart failure and, 68, 69f Left ventricular failure, carotid pulse associated with, 36-38, 38f Left ventricular hypertrophy aortic stenosis with, 84-85 concentric vs. eccentric, 68 electrocardiography in, 49f, 50, 50t hypertension with, 186 in hypertrophic cardiomyopathy, 151-152 Left ventricular noncompaction, 150t Left ventricular outflow tract obstruction congenital, 77-79 in hypertrophic cardiomyopathy, 152 Legionella, 957, 959t, 994 Leishmaniasis, 1038, 1039t Lenalidomide for 5q–syndrome, 506 for multiple myeloma, 552 Length-time bias, 600-601 Lennox-Gastaut syndrome, 1146-1147, 1150-1151 Lepirudin, in heparin-induced thrombocytopenia, 586 Leptin, 630-631 anorexia nervosa and, 635-636 Leptospirosis, 885, 912t, 914 meningitis in, 914, 937 Leriche syndrome, 38, 165 Lesch-Nyhan syndrome, 864 Leukemia acute, classification and common features of, 513-514, 513t-514t acute lymphoblastic, 513-514, 513t-515t, 517-518 tonsillitis associated with, 950 acute myeloid, 513-517, 513t-515t myelodysplastic syndrome and, 503-505, 515 in severe congenital neutropenia, 537 Sweet syndrome in, 878 acute promyelocytic, 515, 517 chemotherapy for neutropenia secondary to, 1030-1031 pulmonary infiltrates and, 1031, 1032f chronic lymphocytic, 548-549, 549t heavy-chain disease with, 553 M proteins in, 550-551, 550t chronic myelogenous, 507, 511-513 leukocyte alkaline phosphatase in, 536 stem cell transplantation for, 500, 513 tyrosine kinase inhibitor for. See Imatinib (Gleevec). fever associated with, 922 fungal infections associated with, 1031 future prospects for, 518b hairy cell, 549, 878 hepatic abscesses in, 975 large granular lymphocyte, 537 rheumatic manifestations of, 878

Index Leukemoid reaction, 512, 535-536 Leukocyte adhesion deficiencies, 533, 1030 Leukocyte count, 535-536 Leukocytoclastic vasculitis, 862, 878 Leukocytosis, 535-536 Leukoencephalitis, acute hemorrhagic, 1170 Leukoencephalopathy progressive. See Progressive multifocal leukoencephalopathy. reversible syndrome of, 1131 Leukoerythroblastic peripheral blood smear, 535-536 Leukopenia, 535-538 in systemic lupus erythematosus, 835, 837t Leukostasis, 514-515 Leukotriene inhibitors, for asthma, 223-224 Leuprolide, for prostate cancer, 626-627 Levetiracetam, 1149-1150, 1150t Levine sign, 32-33 Levo-α-acetylmethadol, 1229 Levodopa for Parkinson disease, 1112-1113, 1112t for primary dystonias, 1114, 1115t Levosimendan, in heart failure, 73 Levothyroxine for goiter, 676-677 for hypothyroidism, 676 subclinical, 676 thyroid nodules and, 677 Lewy bodies, 1074, 1109-1111, 1113 LH. See Luteinizing hormone (LH). LHRH. See Luteinizing hormone–releasing hormone (LHRH) analogues. Libman-Sacks lesions, 963 in antiphospholipid antibody syndrome, 841 in systemic lupus erythematosus, 835 Licorice, mineralocorticoids and, 314, 688 Liddle syndrome, 178, 296, 321 Liddle test. See Dexamethasone suppression test. Lifestyle modification. See also Risk factor modification. for blood pressure reduction, 179, 184 for cancer prevention, 598-600, 599t in diabetes mellitus, 704-706, 708 for dyslipidemia, 646, 646t for weight loss, 632, 632t Li-Fraumeni syndrome, 595-596 Light-chain cast nephropathy, 335 Light-chain disease, 551 Light-chain nephropathy, 331 Likelihood ratio, 17-18 Limbic system, seizures associated with, 1143 Linear scleroderma, 847 Linitis plastica, 607 Linkage analysis, 9, 10f, 11 Linkage disequilibrium, 7-8 Lipase pancreatic, 643 serum in acute pancreatitis, 448 in chronic pancreatitis, 451 Lipids, 643 metabolism of, 643-644, 644f Lipodystrophy, 648t Lipoma, cardiac, 156 Lipoprotein(a), 648-649 cardiovascular risk and, 97 Lipoprotein lipase, 643, 644f, 646 deficiency of, 649-650 Lipoproteins, 643. See also Dyslipidemia; High-density lipoprotein (HDL); Low-density lipoprotein (LDL). classes of, 643, 644t metabolism of, 643-644, 644f Liraglutide, 714 Listeria monocytogenes infection, 886 bacteremia in, 912t, 913 meningitis caused by, 935-936 Literature. See Research studies. Lithostathine, 450-451 Lithotripsy, extracorporeal shock-wave, 343-344 Liver. See also Hepatic entries. abscesses of, 921, 975-976, 976t anatomy and histology of, 488, 489f bile production by, 488 vascular disease of, 485

Liver biopsy, 458-459, 458f in Budd-Chiari syndrome, 486 fibrosis and, 459b Liver disease. See also Cirrhosis; Hepatic failure; Hepatitis. bleeding in, 577 in fulminant hepatic failure, 476-477, 477t end-stage, hypercalcemia in, 787 laboratory tests in, 456-459, 457t, 458f future prospects for, 459b polycystic, 338 volume excess in, 307 Liver dysfunction, in sepsis syndrome, 929 Liver fluke, 493 Chinese, 1040 Liver function tests, 456, 457t, 458f in HIV-infected patients, 1024 Liver transplantation, 485 for Budd-Chiari syndrome, 486 for fulminant hepatic failure, 476-477 for hepatocellular carcinoma, 484-485, 609 for hepatopulmonary syndrome, 484-485 for hepatorenal syndrome, 483 for primary sclerosing cholangitis, 493 for Wilson disease, 652 Loa loa infection, 1040, 1040t Locked-in syndrome, 1062, 1062t, 1127 Löffler syndrome, 239-240 Löfgren syndrome, 232-233, 232t, 882 Long QT syndrome, 143, 143t Long-term care, 1207 Loop diuretics. See also Furosemide. for cirrhotic ascites, 482 in heart failure, 72 refractory, 73 for hyponatremia, hypervolemic hypotonic, 72 mechanism of action, 307-308, 308t Loop of Henle functions of, 292-293, 292f-293f, 296 inherited salt-wasting syndromes and, 314-316 structure of, 286-290, 287f Looser zones, 797-798, 799f Losartan, for Raynaud phenomenon, 847 Loss of consciousness. See Syncope. Low back pain, 1094-1095, 1094t-1095t Low-density lipoprotein (LDL), 643-644, 644f-645f, 644t genetic disorders affecting, 648-650 Low-density lipoprotein (LDL) cholesterol in coronary artery disease, 97, 102 secondary prevention and, 116-117 in diabetes management, 704 dyslipidemia and diagnostic approach, 644-645, 645t management of, 645-647, 646t-647t specific causes, 648-650, 648t hypertension and, 180 lipid metabolism and, 643-644 in metabolic syndrome, 631-632 in peripheral arterial disease, 166 Lower motor neuron diseases. See also specific diseases. clinical spectrum of, 1173, 1173t signs and symptoms of, 1172, 1172t Lown-Ganong-Levine pattern, 128f, 129 LSD (lysergic acid diethylamide), 1225t-1228t, 1231-1232 Ludwig angina, 950 Lumbar puncture, 933, 1054-1055. See also Cerebrospinal fluid (CSF). in comatose patient, 1059 complications of, 1054-1055 contraindications to, 1054-1055 in demyelinating neuropathy, 1178 headache secondary to, 1092 for idiopathic intracranial hypertension, 1092 indications for, 1054-1055, 1056t with suspected brain tumor, 1155 Lumbosacral plexopathy, 1174 Lung(s), 188-191 abscess(es) of, 248, 256 allergens affecting, 194 anatomy of, 198-199, 199f conducting zone of, 198-199 development of, 188-189, 189f, 189t, 191b hyperinflation of, 213, 216-217

1261

Lung(s) (Continued) infectious diseases of, 190-191, 254-258. See also Pneumonia. interstitium of, 226, 227f neoplastic disorders of, 190-191. See also Lung cancer. perfusion of, 203-204, 203f physiology of. See Respiratory physiology. respiratory zone of, 198-199 solitary pulmonary nodule in, 269-270 toxic and environmental exposures of, 194, 225-226, 237-238. See also Hypersensitivity pneumonitis; Pneumoconioses. Lung biopsy, 197 in immunocompromised host, 1031-1032, 1032f Lung cancer, 266-271, 603-605 clinical presentation of, 267, 603-604 epidemiology of, 266, 603 future prospects for, 271b genetics of, 603 histologic classification of, 266, 603 hypertrophic osteoarthropathy in, 878 management of, 268-269, 604-605, 605t preoperative evaluation in, 270-271 tyrosine kinase inhibitors in, 625-626, 626t mediastinal adenopathy in, 251, 268 non–small cell, 266-269, 603-605, 604t-605t paraneoplastic syndromes in, 267-268, 268t, 270 pathogenesis of, 266-267 physical examination and, 194-195 positron emission tomography of, 211, 268 screening for, 268 small cell, 266-269, 603-605, 604t-605t Lambert-Eaton syndrome and, 1192-1193 solitary pulmonary nodule and, 269-270 staging of, 268-270, 269t, 604, 604t Lung injury, acute, 262 in idiopathic pulmonary fibrosis, 230 Lung transplantation for bronchiolitis obliterans, 220 bronchiolitis obliterans secondary to, 219-220 for cystic fibrosis, 221-222 for emphysema, 219 for idiopathic pulmonary fibrosis, 230 for interstitial lung disease, in systemic sclerosis, 848 for lymphangioleiomyomatosis, 239 for nonspecific interstitial pneumonia, 231 for pulmonary hypertension arterial, 170 idiopathic, 243-244 Lung volume reduction surgery, 219 Lung volumes in interstitial lung diseases, 226, 227f measurements of, 195-197, 206-209, 207f-208f in obstructive lung diseases, 213, 216-217 Lupus. See also Systemic lupus erythematosus. drug-induced, 234 neonatal, 838-839 Lupus anticoagulant, 356, 356t, 585, 841 digital ulcerations associated with, 848 tests for, 564-565, 587, 842 thrombocytopenia with, 568-569 Lupus nephritis, 324-326, 326t, 835, 837t, 838 Lupus pernio, 232-233, 233t Lusitropy, 28 Luteinizing hormone (LH), 660, 662t, 666 in male, 691, 692f menstrual cycle and, 732f, 733 Luteinizing hormone–releasing hormone (LHRH) analogues, for prostate cancer, 626-627, 765 LVEF. See Ejection fraction, left ventricular (LVEF). Lyme disease, 885, 917 arthritis in, 987 cardiac manifestations of, 148-149 central nervous system manifestations of, 939, 1177 peripheral neuropathy in, 1177 vs. rheumatoid arthritis, 826 Lymph node biopsy, 541-542 in infectious process, 553-554 Lymph nodes, 540, 541f Lymphadenopathy causes of, 541, 541t, 553-554 febrile syndromes with, 917-920, 918t Lymphangioleiomyomatosis, 226, 228t-229t, 239 Lymphatic circulation, 30

1262

Index

Lymphatic filariasis, 1040 Lymphoblastic lymphoma, 545-546 Lymphocytes, 539-554. See also B lymphocytes; T lymphocytes. Lymphocytic choriomeningitis, 937 Lymphocytic gastritis, 418 Lymphocytic myocarditis, acute, 149 Lymphocytic thyroiditis. See Hashimoto thyroiditis. Lymphocytosis, 535-536 heterophil-negative atypical, 917-918, 918t reactive, 553-554 Lymphogranuloma venereum, 920, 999t, 1006-1007 Lymphoid follicles, 540, 541f Lymphoid interstitial pneumonia, 227-231 Lymphoid neoplasia, 541-542. See also Hairy cell leukemia; Hodgkin disease; Leukemia, acute lymphoblastic; Leukemia, chronic lymphocytic; Lymphoma; Non-Hodgkin lymphoma; Plasma cell disorders. classification of, 541, 542t clinical presentation of, 541 diagnosis of, 541-542 future prospects for, 554b Lymphoid system, 540-541 Lymphoma. See also Lymphoid neoplasia; Mucosaassociated lymphoid tissue (MALT) lymphoma; Non-Hodgkin lymphoma. central nervous system, primary, 1022, 1023t, 1157 in HIV-infected patients, 1026, 1157 1,25-dihydroxyvitamin D secretion by, 785 fever associated with, 922 fungal infections associated with, 1031 gastric, 416-417, 440 mediastinal involvement in, 251 Mediterranean, 553 peripheral T-cell, 545 post-transplantation lymphoproliferative disorder as, 553 rheumatic manifestations of, 878 in Sjögren syndrome, 855 Lymphoproliferative disorder, post-transplantation, 553 Lynch syndrome, 596, 612 Lysosomal storage diseases, hypertrophic cardiomyopathy in, 152 M M proteins, 550-554, 550t Machinery murmurs, 44, 44t Macroalbuminuria, in diabetes, 704, 717 Macrocytic anemia, 522t, 523-526 Macrophage colony-stimulating factor (M-CSF), 535 Macrophages fever and, 910-911, 911f functions of, 535, 892 progenitors of, 497-498, 498f, 535 Macula densa, 286-289, 287f, 292 Magnesium. See also Hypermagnesemia; Hypomagnesemia. deficiency of causes of, 781-782 hypocalcemia secondary to, 790 symptoms of, 781, 782b fluid compartments and, 305, 306f hypokalemia and, 314 intestinal absorption of, 781-782 for migraine prevention, 1088 physiologic roles of, 781 renal handling of, 293, 316, 782 Gitelman syndrome and, 321 renal losses of, excessive, 794 serum, regulation of, 781-782, 782f skeletal fluxes of, 782 for torsades de pointes, 143 units of measurement for, 781 Magnesium sulfate, for preeclampsia, 352 hypermagnesemia caused by, 793 Magnetic resonance angiography (MRA), 60-61 in deep venous thrombosis, 171 gadolinium toxicity in, 371-372 of head and neck, 1056 in mesenteric ischemia, 406 in peripheral arterial disease, 65, 166

Magnetic resonance angiography (MRA) (Continued) renal, 303 of renal artery stenosis, 347, 349f Magnetic resonance cholangiopancreatography (MRCP), 406, 494b in chronic pancreatitis, 451-452 of gallstones, 491 in jaundice evaluation, 464b Magnetic resonance enterography, 433 Magnetic resonance imaging (MRI) of abdomen and pelvis, 406 in acute pancreatitis, 448 of aortic coarctation, 80, 80f of atrial septal defect, 76-77 of brain abscesses, 1159, 1160f of brain tumors, 1155 in cardiovascular disease, 60-61, 62f-63f vs. computed tomography, 1056t in Creutzfeldt-Jakob disease, 1163-1164, 1163f dobutamine stress, 276 in epilepsy, 1147-1148 gadolinium toxicity in, 371-372 in multiple sclerosis, 1166, 1167t, 1168f, 1169 of musculoskeletal disease, 821 in myocarditis, 149 of myopathy, 852-853 in neurologic disease, 1056, 1056t of osteomyelitis, 987 of pituitary tumors, 660, 687 of prostate, 764 renal, 303 of cysts, 337 in respiratory disorders, 197, 210-211 of spinal cord tumors, 1157-1158 of spinal epidural abscess, 1161-1162, 1161f in stroke, 1128, 1129f of subdural empyema, 1160-1161 Magnetic resonance venography, of renal vein thrombosis, 356-357, 357f Major histocompatibility complex (MHC) proteins, 499-500, 539-540. See also Human leukocyte antigen (HLA) proteins. Malabsorption, 389-395 approach to patient with, 393-394, 393f in chronic pancreatitis, 452 clinical manifestations of, 391, 392t clinical tests for, 391-393, 393t diarrhea secondary to, 399-400 in inflammatory bowel disease, 432, 437 kidney stone formation and, 342 pathophysiologic mechanisms of, 390-391, 390t physiologic basis of, 389-390 specific disorders with, 390t, 392t, 394-395 as therapy for obesity, 395 Malaria, 889t, 1039t differential diagnosis of, 1037 febrile syndrome in, 915, 1037 hypoglycemia in, 724 prophylaxis against, 1035-1036 treatment of, 1037 Maldigestion, 390, 394 Male reproductive endocrinology, 691-696, 696b. See also Gynecomastia; Hypogonadism; Infertility. Malignant hyperthermia, 1084, 1186t, 1188 Malignant middle cerebral artery syndrome, 1131 Malingering, 1082 Malnutrition. See also Nutritional deficiencies; Nutritional support. in acute or chronic illness, 638 hypoglycemia in, 724 hypomagnesemia in, 794 in obstructive lung disease, 219 in older adults, 1205-1206 MALT. See Mucosa-associated lymphoid tissue (MALT). Mammography diagnostic, 746-747 screening, 734t Manganese intoxication hypercalcemia in, 787 parkinsonism secondary to, 1114 Mania, 1077-1080, 1078t Mannitol, for elevated intracranial pressure, 1137 tumor-associated, 1156 Mantle cell lymphoma, 545

Marantic endocarditis, 571, 963 in Trousseau syndrome, 171 Marfan syndrome β blockers in, for aortic root enlargement, 167-168 pregnancy with, 163 Marginal zone lymphomas, 545 Margination of monocytes, 535 of neutrophils, 533, 535 Marijuana, 1225t-1228t, 1231 xerophthalmia and xerostomia caused by, 857 Mastitis, 747 Maturity-onset diabetes of the young, 700 Maze procedure, for atrial fibrillation, 126-127 M-CSF (macrophage colony-stimulating factor), 535 MDMA (3,4-methylenedioxy methamphetamine), 1232-1233 heat stroke caused by, 1084 Mean corpuscular volume (MCV), 521f, 522, 522t Measles, immunization of travelers against, 1035 Mechanical circulatory assist devices, 73-74. See also Ventricular assist devices. Mechanical ventilation, 259-261. See also Intubation, endotracheal. in acute respiratory distress syndrome, 262 in acute respiratory failure, 259-260 common problems in, 261 complications of, 261-262 pneumothorax as, 250 invasive, 260-261 noninvasive, 260 in pneumonia, 958-959 pneumonia associated with, 255, 994-995 removal of, in brain death, 1063 right-to-left shunt and, 206 for status asthmaticus, 224 stress bleeding prophylaxis in, 418 in traumatic spinal cord injury, 1139 weaning from, 261-262, 261t critical illness myopathy and, 1190 Meckel diverticulum, radionuclide studies of, 407 Median-chain triglycerides, 452 Mediastinal disease, 251, 251f, 253b in lung cancer, 267-268 Mediastinitis, 251 Mediastinum, 251, 251f Mediterranean lymphoma, 553 Medullary cystic kidney disease, 339 Medulloblastoma, 1157, 1158b Mefloquine, for malaria prophylaxis, 1035-1036 Megacolon, toxic, 431 Megakaryocytes, 497-498 decreased production of, 566 diagnostic evaluation of, 566-568 Megaloblastic anemia, 521f, 522t, 523-526 Meglitinides, 710t-713t, 714 hypoglycemia caused by, 723-724 Meige syndrome, 1115t Melanocortin, appetite and, 631 Melanoma, 614 MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes), 1187 Melatonin, for sleep disorders, 1066 Melena, 385, 387-388 Membranoproliferative glomerulonephritis, 330, 332 Membranous glomerulonephritis, 328-329, 328f, 332 renal vein thrombosis in, 357f Memory. See also Amnesia; Dementia. aging and, 1076 structure of, 1075-1076 MEN. See Multiple endocrine neoplasia (MEN) syndrome type I; Multiple endocrine neoplasia (MEN) syndrome type II. Men who have sex with men (MSM) chlamydia in, 1004 giardiasis in, 1038 gonorrhea in, 1003 herpes simplex virus and, 1000 HIV infection in, 1008-1009 human papillomavirus and, 1006, 1021 proctocolitis in, 1006-1007 syphilis in, 998, 1000-1001 Ménétrier disease, 419 Ménière disease, 1102, 1104-1105, 1105t Meningeal carcinomatosis, 939

Index Meningeal irritation, in coma, 1058 signs of, 1059, 1061f Meningioma, 1157 Meningismus, 1091 Meningitis, 934-939. See also Meningoencephalitis. acute bacterial, 934-937 clinical presentation of, 935 coma in, 1058-1059, 1061f CSF rhinorrhea and, 945-946 differential diagnosis of, 936 epidemiology of, 934 headache in, 1092 initial evaluation of, 933-934, 934t laboratory diagnosis of, 935-936 pathogenesis of, 934-935 pathogens in, 934, 935t recurrence of, 936, 937t treatment of, 936-937 aseptic, 937-938, 937t in HIV-infected patients, 937, 1014, 1022 fungal, 942 cryptococcal, 888, 938, 942 headache with, 1091 immune response modifiers implicated in, 942-944, 943t infective endocarditis complicated by, 962-963, 967 laboratory diagnosis of. See also Cerebrospinal fluid (CSF). with India ink preparation, 898, 899f, 938-939 with microbial antigens, 898-899, 899t pneumonia with, 952 subacute and chronic, 938-939, 938t in HIV-infected patients, 938, 1022-1023 Meningococcal infection. See Neisseria meningitidis infection. Meningococcal vaccine for splenectomized patients, 1030 for travelers, 1034-1035 Meningococcemia, fever and rash in, 915, 935 Meningoencephalitis in HIV-infected patients, 1023 in immunocompromised patients, 935t infective endocarditis complicated by, 962 viral etiologies of, 937t West Nile virus causing, 940-941 Menopause and perimenopause, 733, 742t Men’s health, 752-769 benign scrotal diseases in, 768-769 erectile dysfunction in. See Erectile dysfunction. penile carcinoma in, 765-766 prostate in. See Benign prostatic hyperplasia (BPN); Prostate cancer; Prostatitis. reproductive endocrinology and, 691-696, 696b. See also Gynecomastia; Hypogonadism; Infertility. testicular cancer in, 611t, 766-767, 766t Menstrual cycle, 732f, 733. See also Amenorrhea. abnormal, 740-741, 740t in perimenopause, 742, 742t epilepsy and, 1141 Meperidine abuse of, 1225t-1228t, 1229 abused derivatives of, 1232 Mercaptopropionylglycine, for cystinuria, 344 Mercaptopurine, for inflammatory bowel disease, 436-437 MERRF (myoclonic epilepsy and ragged red fibers), 1187 Mesalamine, for inflammatory bowel disease, 436 Mesangium, 288-289, 288f chronic kidney disease and, 369-370, 374-375 Mescaline, 1225t-1228t, 1231 Mesenteric ischemia, imaging in, 406 Mesial temporal sclerosis, 1145, 1147-1148 Mesothelioma, 250-251 Mesothelium, pleural, 248 Messenger RNA (mRNA) splicing of, 3-4 synthesis of, 2-4, 3f translation of. See Translation. Meta-analyses, 16-17 Metabolic acidosis, 317-319. See also Acidosis; Renal tubular acidosis. in acute tubular necrosis, 364 causes of, 318, 318t

Metabolic acidosis (Continued) in chronic kidney disease, 375 hyperchloremic. See Hyperchloremic metabolic acidosis. osteomalacia and rickets in, 798 potassium and, 312, 314, 314f Metabolic alkalosis, 314, 314f, 320-321 in primary aldosteronism, 688 Metabolic syndrome, 700-701. See also Insulin resistance. coronary artery disease and, 97 definition of, 96-97, 631-632 obesity and, 631-632 osteoarthritis and, 870 sleep apnea and, 245 treatment of, 715 women’s health and, 746 Metapharyngitic hematuria, 325 Metformin, 709-712, 710t-713t in gestational diabetes, 706 in metabolic syndrome, 715 for prevention of type 2 diabetes, 708-712, 719 Methacholine, in bronchoprovocation testing, 209, 209f, 223 Methadone, 1214t for opioid abuse, 1229 Methamphetamine. See Amphetamines. Methotrexate, 623t for inflammatory bowel disease, 436-437 for rheumatoid arthritis, 827 for spondyloarthropathies, 832 for systemic lupus erythematosus, 838 for systemic sclerosis, 848 teratogenicity of, 863 Methyldopa, for hypertension, in pregnancy, 184, 352 Methylprednisolone for immune thrombocytopenic purpura, 569 for multiple sclerosis, 1167 for neuromyelitis optica, 1169 for optic neuritis, 1169 in traumatic spinal cord injury, 1138-1139 Metoclopramide, for gastroparesis, 428 Metolazone, 307-308, 308t Metoprolol in heart failure, 73 after myocardial infarction, 111 perioperative, with noncardiac surgery, 279 Metronidazole, in inflammatory bowel disease, 436 Metyrapone test, 662t, 664 MGUS. See Monoclonal gammopathy of unknown significance (MGUS). MHC. See Major histocompatibility complex (MHC) proteins. Microalbuminuria in diabetes, 329, 704, 717 kidney damage and, 300 Microangiopathy, thrombotic, 331-332, 332t, 352-357, 353t, 354f-355f, 586-587 in antiphospholipid antibody syndrome, 356, 841-842 Microarrays, DNA, 11, 13, 14b Microbial antigens, detection of, 898-899, 899t, 900f Microcytic anemia, 521f, 522-523, 522t β2-Microglobulin amyloidosis associated with, 880 in end-stage renal disease, 373 in iron metabolism, 653 in multiple myeloma, 551-552 MicroRNAs (miRNAs), 5 Microscopic polyangiitis, 236, 327, 859f, 860 Microsporidial infection, 889t in HIV-infected patients, 1024-1025, 1025t Microvascular coronary disease, 98 Middle cerebral artery, stroke associated with, 1126-1127, 1127t, 1131 Miglitol, 710t-713t, 712 Migraine, 1086-1088, 1087t, 1089f aura of, 1087-1088, 1149 causes of, 1087-1088 classification of, 1087, 1087t clinical features of, 1086-1087 complicated, 1087

1263

Migraine (Continued) differential diagnosis of, 1088t vs. seizures, 1149 vs. sinusitis, 1091 vs. tension headache, 1090t dizziness in, 1106-1107, 1107b epidemiology of, 1087 in fibromyalgia syndrome, 876 hemiplegic, 1128 vs. Ménière disease, 1105 patent foramen ovale and, 1095b prevention of, 1088, 1090t treatment of, 1088, 1089f Migrating motor complex, 416 Migratory thrombophlebitis. See Trousseau syndrome. Mild cognitive impairment, 1201-1202 Milk-alkali syndrome, 321, 786-787 Milkman pseudofractures, 797-798, 799f Millard-Gubler syndrome, 1126 Milrinone, for heart failure, refractory, 73 Mineralocorticoid deficiency. See also Hypoaldosteronism. in adrenal insufficiency, 680-683, 682t in congenital adrenal hyperplasia, 683-684 Mineralocorticoid excess, 684, 684t, 688-689, 688f Mineralocorticoid replacement, for adrenal insufficiency, 683 Mineralocorticoids. See Aldosterone. Minimal change disease, 327-328 Minimally invasive surgery, cardiac, 159 Mini-Mental State Examination, 1072, 1073t, 1201-1202 Minute ventilation, 199-200 Mirizzi syndrome, 463-464, 490-492, 490f miRNAs (microRNAs), 5 Misoprostol, for gastroduodenal ulcer prophylaxis, 424-425 Missense substitutions, 7 Mitgehen, 1109 Mitochondrial diseases hypertrophic cardiomyopathy in, 152 myopathies, 1186t, 1187 Mitochondrial DNA, disorders associated with, 12, 1186t, 1187 Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), 1187 Mitoxantrone, for multiple sclerosis, 1167-1169 Mitral regurgitation, 86t, 89-90 acute papillary muscle rupture with, 116 severe, 90 atrial septal defect with, 75 color Doppler echocardiography of, 57f with heart failure, 74b in hypertrophic cardiomyopathy, 152 mitral valve prolapse with, 90-91 murmur of, 43 noncardiac surgery in patient with, 281 Mitral stenosis, 86t, 87-89, 88f noncardiac surgery in patient with, 162, 281 opening snap of, 41-42, 42f pregnancy in patient with, 162-163 Mitral valve anatomy of, 22 fibroelastoma of, 156 opening of, 27f prosthetic, transesophageal echocardiography of, 58f Mitral valve commissurotomy, 89 Mitral valve prolapse, 89-91, 89f autosomal dominant polycystic kidney disease with, 338 systolic click of, 41, 42f Mitral valve repair, 90 percutaneous, 74b Mitral valve replacement, 89-90 Mixed venous Po2, 206, 207f Mixing study, of plasma, 564-565, 565f, 565t Mobitz type I atrioventricular block, 123 Mobitz type II atrioventricular block, 123 Modafinil, 1066, 1066t Molds. See Fungal pathogens. Molecular diagnostics, 10-11, 14b Molecular medicine, 2-14, 14b Molluscum contagiosum, in HIV-infected patients, 1020t

1264

Index

Monoclonal antibodies, as anticancer agents, 625, 626t, 627 Monoclonal gammopathy of unknown significance (MGUS), 550-551, 550t peripheral neuropathy with, 1177-1178 Monocytes fever and, 534f, 535 normal structure and function of, 534f, 535 progenitors of, 497-498, 498f Monogenic disorders, 11-12, 11t Mononeuritis multiplex, 1176 Mononeuropathy multiplex, 1174-1175 Mononucleosis, infectious, pharyngitis in, 948 Mononucleosis syndromes, 912, 917-919, 918t Monospot test, 918-919, 918t, 922 Mood disorders, 1077-1080, 1078t-1079t. See also Depression. Moraxella catarrhalis, 886 Morphea, 847, 847t Morphine, 1214t in acute myocardial infarction, 110-111 Mosaic haplotypes, 7-8 Motility disorders, in traumatic spinal cord injury, 1139 Motility disorders, gastrointestinal. See also Gastric emptying. esophageal, 411-412, 412f, 412t dysphagia in, 411 reflux and, 409 intestinal, diarrhea secondary to, 397t, 398 in systemic sclerosis, 412, 412t, 846, 846t, 848t, 849 Motor neuron diseases, 1171-1174 classification of, 1171, 1172t-1173t clinical features of, 1171, 1172t specific diseases amyotrophic lateral sclerosis, 1171-1173, 1173t bulbospinal muscular atrophy, 1173-1174 primary lateral sclerosis, 1173 progressive muscular atrophy, 1173 spinal muscular atrophy, 1173 symptom management for, 1173t Motor system, anatomy of, 1108-1109, 1109f-1111f Motor system disorders, 1108-1118 anatomic classification of, 1108, 1110t future prospects for, 1117b hyperkinetic, 1109, 1111t, 1114-1116 hypokinetic, 1109-1114, 1111t signs and symptoms of, 1108 cerebellar system and, 1109, 1111t extrapyramidal system and, 1109 Mouth. See Oral cavity. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), 1232 MRA. See Magnetic resonance angiography (MRA). MRCP. See Magnetic resonance cholangiopancreatography (MRCP). MRI. See Magnetic resonance imaging (MRI). mRNA. See Messenger RNA (mRNA). MRSA. See Staphylococcus aureus infection, methicillinresistant (MRSA). MSM. See Men who have sex with men (MSM). Mucorales, 888 pulmonary infiltrates caused by, 1031 sinusitis caused by, 946 Mucormycosis. See Mucorales. Mucosa-associated lymphoid tissue (MALT), 540 Mucosa-associated lymphoid tissue (MALT) lymphoma, 545 Helicobacter pylori infection and, 416-417, 440, 542-543, 545 Mucositis, cancer therapy–induced, 627 Müllerian agenesis, 735-736 Multifocal atrial tachycardia, 125, 125f Multiple endocrine neoplasia (MEN) syndrome type I gastronomas in, 426-427 hyperparathyroidism in, 785 Multiple endocrine neoplasia (MEN) syndrome type II hyperparathyroidism in, 785 medullary thyroid carcinoma in, 677-678 pheochromocytoma in, 689 Multiple myeloma, 550-552, 550t-551t hypercalcemia in, 787 monoclonal gammopathy progressing to, 550-551 musculoskeletal manifestations of, 879-880

Multiple myeloma (Continued) renal dysfunction in, 330-331, 335, 551-552 skeletal demineralization in, 800 Multiple sclerosis, 1165-1169 clinically isolated syndrome (CIS) in, 1165, 1167, 1169 diagnosis of cerebrospinal fluid in, 1165-1166, 1168f criteria for, 1166, 1167t magnetic resonance imaging in, 1166, 1167t, 1168f symptoms and signs in, 1166, 1166t visual evoked potentials in, 1166, 1167t differential diagnosis of, 1166, 1168t epidemiology of, 1165 etiology of, 1165 pathology of, 1165 progressive, 1165, 1167-1169, 1168t relapsing-remitting, 1165, 1167-1169, 1168t treatment of, 1167-1169, 1169t Multiple-organ failure, 263 acute respiratory distress syndrome with, 262 in severe sepsis, 925-928, 926f Multisystem atrophy, 1113-1114 Mumps, 937 arthritis secondary to, 986 Munchausen syndrome, 924, 1082 Murine typhus, 916 Murmurs, 42-44, 43f in acute coronary syndrome, 106 in angina episode, 99 in aortic coarctation, 79-80 of aortic regurgitation, 87 acute, 87 of aortic stenosis, 84 of atrial septal defect, 76 of bicuspid aortic stenosis, 78 classification of, 43, 44t in dilated cardiomyopathy, 151 grading of, 42-43, 42t in heart failure, 70 in hypertrophic cardiomyopathy, 152 in infective endocarditis, 962 innocent, 39-40, 43 maneuvers affecting, 40t of mitral regurgitation, 90 of mitral stenosis, 88 of mitral valve prolapse, 90-91 of papillary muscle rupture, 116 of patent ductus arteriosus, 80 physiologic, 39-40 of prosthetic valves, 44-45 in pulmonary arterial hypertension, 170 of pulmonic regurgitation, 91 of pulmonic valve stenosis, 79 of subaortic stenosis, 78-79 of tricuspid regurgitation, 91 of tricuspid stenosis, 91 venous hum, 44 of ventricular septal defect, 77 postinfarction, 116 Murphy sign, 491-492 Muscle cardiac, 25, 26f skeletal, 1182 Muscle biopsy in HIV-infected patients, 1026 in hypothyroidism, 882 in idiopathic inflammatory myositis, 852-853, 852f in myopathies, 1184 in peripheral neuropathy, 1178 Muscle contractures, 1182-1183 Muscle cramps, 1182-1183 Muscle diseases. See Myopathy(ies). Muscle infarction, lower extremity, 1190 Muscle infections, 973-974, 973f Muscle relaxants, adverse reactions to, 1193 Muscle stiffness. See Myotonia. Muscle strength, quantitation of, 1183 Muscular dystrophies, 1184, 1185t cardiomyopathies associated with, 150t Musculoskeletal disorders. See also Arthritis; Soft tissue disorders, nonarticular. anatomic locations of, 820f chest pain in, 34t

Musculoskeletal disorders (Continued) evaluation of patient with, 818-822 biopsy in, 821 history and examination in, 818-820, 819t, 820f, 874 laboratory testing in, 820-821, 821t radiographic studies in, 821 summary of, 822 in HIV-infected patients, 1026 Musculoskeletal system, anatomic structures of, 820f Mutation(s), 6-8 definitions of, 6-8 disease-causing, identification of, 10-14 types of, 7, 7t variability in clinical expression of, 12 Myalgias, 1182-1183 Myasthenia gravis, 1191-1192 clinical trials for, 1193b lung cancer with, 270 thymoma with, 251, 1191-1192 Mycobacteria, 887 laboratory isolation of, 903 molecular diagnostics of, 900 Mycobacterial infections arthritis in, 986-987 cutaneous, 971 fever associated with, 922 immune response modifiers and, 943-944 osteomyelitis in, chronic, 988 Mycobacterium avium complex, 887 in HIV-infected patients diarrhea caused by, 1025, 1025t fever and anemia caused by, 1025 prophylaxis against, 1019-1020, 1019t lymphadenitis caused by, 919 Mycobacterium leprae, 887 Mycobacterium scrofulaceum, lymphadenitis caused by, 919 Mycobacterium tuberculosis. See Tuberculosis. Mycophenolate mofetil, 378, 378f for idiopathic inflammatory myositis, 853-854 for systemic lupus erythematosus, 838 for systemic sclerosis, 848, 848t Mycoplasma pneumoniae, 885 hemolytic anemia associated with, 527-528 pneumonia caused by, 255, 255t, 956, 959t Mycoplasmas, 885. See also Mycoplasma pneumoniae; Ureaplasma urealyticum infection. laboratory isolation of, 902 Mycoses. See Fungal infections. Mycotic aneurysms, 962, 967, 1133, 1162-1163 Myectomy, for hypertrophic cardiomyopathy, 152, 153f Myelodysplastic disorders. See also Hematopoietic failure. peripheral blood smear in, 522f Myelodysplastic syndrome, 503-506, 504t-505t Myelofibrosis causes of, 510, 510t primary, 510-511, 510t thrombocytopenia secondary to, 567 Myeloma. See Multiple myeloma. Myeloma kidney, 335 Myelomeningocele, 1119 Myeloperoxidase antibodies against, 235-237, 327, 860 of neutrophils, 533-534 Myelophthisis, peripheral blood smear in, 535-536 Myeloproliferative neoplasms, 507, 508t, 518b. See also Leukemia; Myelofibrosis, primary; Polycythemia vera; Thrombocythemia, essential. Mylotarg. See Gemtuzumab ozogamicin (Mylotarg). Myocardial infarction cocaine-associated, 97-98, 1230, 1231f complications of, 113-116, 113t electrocardiography in, 51-53, 52f-53f infarct localization with, 53, 54t, 106-107 non–ST-segment elevation, 108, 108f, 110 right ventricular, 115, 115f ST-segment elevation, 106-107, 107f, 110 implantable cardioverter-defibrillator following, 142-143 magnetic resonance imaging in, 63f myocyte metabolism in, 25 nausea and vomiting in, 35 nonatherosclerotic causes of, 97-98, 106

Index Myocardial infarction (Continued) non–ST-segment elevation (NSTEMI), 106-107 electrocardiography in, 108, 108f, 110 plaque disruption and, 95 treatment of, 108-110, 109f pain of, 32-33, 33t plaque disruption and, 95 postoperative, 161-162, 274 analgesia and, 279-280 management of, 280-281 monitoring for, 280 right ventricular, 110-111, 115, 115f secondary prevention of, 116-117 silent, 107, 731 ST-segment elevation (STEMI), 106 complications of, 111-112 electrocardiography in, 106-107, 107f, 110 pathophysiology of, 95, 110 treatment of, 109f, 110-112 sudden cardiac death following, 135, 135t, 142-143 systemic lupus erythematosus and, 839 ventricular tachyarrhythmias associated with, 130-131 Myocardial ischemia. See also Angina pectoris. asymptomatic (silent), 35 cocaine-induced, 97-98, 1230, 1231f coronary artery anomalies and, 82-83 dyspnea in, 33 electrocardiography in, 51-53 in hypertrophic cardiomyopathy, 152 nonatherosclerotic, 97-98, 106 nuclear perfusion imaging of, 57-58 pathophysiology of, 98 stress testing in, 53-55 subendocardial, 106 Myocardial necrosis, 107-108, 110 in fatal infarction, 114 Myocardial oxygen consumption, 28-29 exercise and, 31 Myocardial perfusion imaging magnetic resonance, 60-61, 63f radionuclide. See Nuclear myocardial perfusion imaging. Myocarditis, 148-149 acute lymphocytic, 149 future prospects for, 155b magnetic resonance imaging in, 63f in systemic lupus erythematosus, 835 Myocardium cellular structure of, 25, 25f metabolism of, 25 Myoclonic epilepsy and ragged red fibers (MERRF), 1187 Myoclonic seizures, 1146 Myoclonus, 1111t, 1115-1116 Myocytes, cardiac contraction of, 25, 26f experimental replacement of, 74b structure of, 25, 25f Myofibrils cardiac, 25, 25f skeletal muscle, 1182 Myoglobinuria, 367, 1190 in chronic alcoholics, 1190 in glycogenoses, 1185-1186 in malignant hyperthermia, 1188 in neuroleptic malignant syndrome, 1188 Myonecrosis, 973-974, 973f Myopathy(ies), 1182-1190 assessment of, 1182-1184 channelopathies, 1186t, 1187-1188 epilepsy in, 1142 classification of, 1171, 1172t, 1182 clinical features of, 1171, 1172t congenital, 1184-1185, 1185t definition of, 1182 electromyography in, 1171 in endocrine and systemic disorders, 1189-1190 hyperthyroidism, 882, 1189-1190 hypothyroidism, 882, 1189-1190 gene therapy for, 1190b HIV-associated, 1026, 1189 inflammatory, 1188-1189, 1188t-1189t. See also Myositis. metabolic, 1185-1187, 1186t mitochondrial, 1186t, 1187

Myopathy(ies) (Continued) muscular dystrophies, 1184, 1185t cardiomyopathies associated with, 150t myoglobinuria in. See Myoglobinuria. neuroleptic malignant syndrome, 1084, 1188 stiff-person syndrome, 1188 toxic, 1190, 1190t Myosin, of cardiac myocytes, 25, 25f-26f Myositis acute inflammatory, 820, 820f idiopathic, 850-854, 1188-1189, 1189t autoantibody profiles of, 850, 851t classification of, 850, 851t clinical presentation of, 851-852, 852t diagnosis of, 852-853, 853t differential diagnosis of, 853, 853t epidemiology of, 850 pathology and pathophysiology of, 850, 852f pulmonary manifestations of, 233-234, 234t, 851, 852t in systemic sclerosis, 846, 846t, 848t, 849 treatment of, 853-854 infectious, 1189, 1189t Myotonia definition of, 1182-1183 electromyography in, 1171 nondystrophic disorders of, 1186t, 1187-1188 Myotonia congenita, 1187 Myotonic dystrophy, 692, 1184, 1185t Myxedema, 675 Myxedema coma, 675-676 Myxoma, cardiac, 156 N Nail thickening, in reactive arthritis, 831 Nalmefene, for alcoholism, 1223-1224 Naloxone, 1229 Naltrexone for alcoholism, 1223 to block opioid abuse, 1229 Narcolepsy, 1066 NASH (nonalcoholic steatohepatitis), 473-474 Nasopharyngeal cancers, 606 Natalizumab for Crohn disease, 437 JC viral encephalitis associated with, 943-944, 943t for multiple sclerosis, 1167-1169 Nateglinide, 710t-713t, 714 Native Americans, gallbladder disease in, 491 Natriuretic peptides, in heart failure, 69 Natural killer cells, 540-541, 893-895, 897 Neck pain, 1093-1094, 1094f, 1094t Neck stiffness cervical spondylosis with, 1093-1094 giant cell arteritis with, 1092 headache with, 1091 Necrotizing fasciitis, 973-974 Necrotizing skin and soft tissue infections, 973-974 Needle aspiration with endoscopic ultrasound guidance, 403-404 transthoracic percutaneous, 197 Negative predictive value, 600 Neglect, hemispatial, 1070 Neisseria gonorrhoeae infection. See Gonorrhea. Neisseria meningitidis infection. See also Meningococcal vaccine. acute meningitis in, 934-937 bacteremia in, 929 immune response to, 896 Neisseria species, 886 Nelson syndrome, 687-688 Nematodes, intestinal, 1039, 1040t Neoadjuvant chemotherapy, 624 Neonatal jaundice, 460, 463, 463t Neonatal lupus, 838-839 Neoplasms. See Cancer; Tumor(s). Neostigmine, for myasthenia gravis, 1192 Nephritic syndromes, acute, 301-302, 301t, 323-327, 324t. See also Rapidly progressive glomerulonephritis (RPGN). Nephritis. See also Glomerulonephritis. hereditary, 330 interstitial. See Interstitial nephritis.

1265

Nephritis (Continued) in systemic lupus erythematosus. See Lupus nephritis. Nephrocalcinosis chronic interstitial nephritis with, 334 metabolic alkalosis with, 321 renal tubular acidosis with, 320 Nephrogenic diabetes insipidus, 306-307, 311, 668, 668t Nephrogenic syndrome of inappropriate antidiuresis, 309 Nephrogenic systemic fibrosis, 371-372, 847, 847t Nephrolithiasis, 340-341 calcium stones in, 342-344, 342t in Crohn disease, 432 cystine stones in, 343-344 etiology of, 341 evaluation in, 341, 341t in gout, 867-868 in hyperparathyroidism, 785 medications associated with, 341t struvite stones in, 343, 343t treatment of, 341, 342t uric acid stones in, 343 in Wilson disease, 651 Nephron, 286-288, 287f. See also Distal nephron; Loop of Henle; Proximal tubule. Nephronophthisis, juvenile, 339 Nephrosclerosis, hypertensive, 182, 331, 336, 350-351 Nephrotic syndromes, 301t, 302, 323-324, 324t, 327-329 hyperlipidemia in, 648t podocyte structure and, 288-289 thrombosis in, 585 renal vein, 356, 357f volume excess in, 307 Nephrotoxins endogenous, 367-368 exogenous, 365-366, 365t Nerve biopsy, 1178 Nerve conduction studies, 1055-1056, 1171 in Lambert-Eaton syndrome, 1192-1193 in myasthenia gravis, 1192 in peripheral neuropathies, 1178 Nervous system. See Central nervous system entries; Peripheral neuropathies. Nesiritide, in heart failure, 73 Neural tube defects, 1119 antiepileptic drugs and, 1151-1152 folic acid and, 739, 1119, 1152 Neurocardiogenic (vasovagal) syncope, 133-134, 133t Neurocutaneous disorders, 1121-1122 Neurodevelopmental disorders, 1119 Neurofibromatosis type 1, 1121 Neurofibromatosis type 2, 1121 Neurogenic shock, 1138-1139 Neuroleptic malignant syndrome, 1084, 1188 Neurologic diseases, categories of, 1054t Neurologic evaluation, 1052-1057 diagnostic tests in, 1054-1057 examination in, 1053-1054, 1055t final common pathways and, 1053-1054, 1056f functional imaging in, 1057b history in, 1052-1053 hypotheses in, 1052 localization in, 1052, 1053t-1054t Neuromuscular blockers, adverse reactions to, 1193 Neuromuscular diseases. See also Motor neuron diseases; Myopathy(ies); Neuromuscular junction disease; Peripheral neuropathies; Plexopathies. cardiomyopathies associated with, 150t classification of, 1171, 1172t clinical features of, 1171, 1172t Neuromuscular junction disease, 1191-1193 botulism, 1193 classification of, 1171, 1172t, 1191, 1192t clinical features of, 1171, 1172t drug-induced myasthenic syndromes, 1193 Lambert-Eaton myasthenic syndrome, 268t, 270, 619t, 1192-1193 myasthenia gravis, 1191-1192 clinical trials for, 1193b lung cancer with, 270 thymoma with, 251, 1191-1192 pathophysiology of, 1191

1266

Index

Neuromyelitis optica, 1099, 1169 Neuronal migration disorders, 1142, 1147-1148 Neuropathic arthropathy, 881 Neuropathic pain, 1178, 1178t Neuropathy. See Peripheral neuropathies. Neuroprotective agents, 1125, 1131, 1135b Neutropenia, 535-538, 536t chemotherapy-associated, 1030-1031 febrile, 616-617, 627, 920t, 923 fungal infection in, 1032 prevention of infections in, 1032-1033 treatment of infections in, 1033 organisms causing infections in, 1030-1031, 1031t prevention of infections in, 1032-1033 sepsis-associated, 929 treatment of infections in, 1033 Neutrophil count, determinants of, 535-536. See also Neutropenia; Neutrophilia. Neutrophilia, 535-536, 536t Neutrophils, 533-538 impaired function of, 1030 normal structure and function of, 533-534, 534f, 892 progenitors of, 498, 498f, 535 New York Heart Association Functional Classification, 35-36, 35t, 69t Nicardipine, in hypertensive emergency, 185, 185t Nicotinic acid (niacin) in diabetes, 704 for hyperlipidemia, 647, 647t lipoprotein(a) and, 648-649 in stable angina, 102 Nifedipine in heart failure, 72 for Raynaud phenomenon, 847 Nightmares, 1066-1067 Nilotinib, 512-513 Nimodipine, after subarachnoid hemorrhage, 1134 Nipple discharge, 746-747 Nitrates for angina pectoris, 103, 103t variant, 106 with hydralazine, for heart failure, 72 phosphodiesterase inhibitors and, 762 Nitric oxide as coronary vasodilator, 29 gastric mucosa and, 419-420 renal sodium transport and, 295 in sepsis, 927, 927f sexual stimulation and, 759-760, 760f, 762 Nitrofurantoin, pulmonary toxicity of, 234, 235t Nitroglycerin for angina pectoris, 32-33, 99, 100f, 103, 103t unstable, 106 in hypertensive emergency, 185, 185t in myocardial infarction non–ST-segment elevation, 108-109 ST-segment elevation, 110-111, 114-115 topical, for Raynaud phenomenon, 847 for unstable angina, 108-109 Nitroprusside in heart failure, refractory, 73 for hypertensive emergency, 185, 185t Nizatidine, for peptic ulcer disease, 423 Nocardia, 887-888 Nodules cutaneous, 969, 971 rheumatoid, 825-826 solitary pulmonary, 269-270 thyroid. See Thyroid gland, nodules of. Nonalcoholic fatty liver disease, 474, 478 Nonalcoholic steatohepatitis (NASH), 473-474 Non-Hodgkin lymphoma, 542-546. See also Lymphoma. classification of, 542, 542t clinical presentation of, 543 etiology of, 542-543 in HIV-infected patients, 553, 1025-1026 staging of, 543-544, 543t systemic lupus erythematosus and, 839 treatment and prognosis of, 544-546 for diffuse aggressive types, 545 for high-grade types, 545-546 for indolent types, 544-545 for mantle cell lymphoma, 545

Non–Q-wave myocardial infarction. See Myocardial infarction, non–ST-segment elevation (NSTEMI). Nonsense substitutions, 7 Nonsteroidal anti-inflammatory drugs (NSAIDs). See also Aspirin. antiplatelet mechanism of, 559 for bursitis, 875 for calcium pyrophosphate deposition disease, 869 for chronic pelvic pain, male, 758 gastroduodenal mucosal injury secondary to, 417 for gout, 867-868, 867t-868t liver biopsy and, 458-459 liver disease secondary to, 472 for menstrual cramping, 733 nephrotoxicity of, 366 for osteoarthritis pain, 872 peptic ulcer disease and, 419-421 treatment and prophylaxis of, 424-425, 425t platelet dysfunction caused by, 572-573, 572t renal water reabsorption and, 296, 305-306 in rheumatoid arthritis, 826-827, 827t for spondyloarthropathies, 832-833 for tendinitis, 875 Nonulcer dyspepsia, 384, 422f, 425-426 Normocytic anemia, 521f, 522t, 526 Norovirus infection, 981-982, 981t Nosocomial infections. See Infections, health care–associated. NSTEMI. See Myocardial infarction, non–ST-segment elevation (NSTEMI). Nuclear imaging. See Radionuclide imaging. Nuclear myocardial perfusion imaging, 55-58, 59f in angina pectoris, 101 delayed enhancement MRI compared to, 60-61 Nucleosome, 5-6, 6f 5′-Nucleotidase, 457, 457t Number needed to treat, 18 Nurses Health Study, 731, 746 Nutrition. See Diet. Nutritional assessment, 638-639, 639t Nutritional deficiencies. See also Malnutrition; specific nutrients. in alcoholic, 1221 dilated cardiomyopathy caused by, 151 sore mouth and throat in, 950 Nutritional requirements, 639, 639t Nutritional supplements, for women, 734t Nutritional support, 639-642, 639t in inflammatory bowel disease, 437 Nystagmus, 1104-1106, 1105t O Obesity, 630-634 assessment of, 630 recommended for women, 734t definition of, 630 epidemiology of, 630 hyperlipidemia in, 648t metabolic syndrome and, 700-701 morbid, 630 nutritional requirements in, 639 pathogenesis of, 630-631, 631f prognosis of, 634 respiratory consequences of, 252 risks associated with, 631-632, 632t cancer, 599 coronary artery disease, 97 sleep apnea, 245-246 treatment of, 632-634, 632t, 633f malabsorptive therapy for, 395 type 2 diabetes and, 702-703, 705 visceral, 630-631 in women, 746 Obesity-hypoventilation syndrome, 246, 252 Obsessive-compulsive disorder, 1080-1081 Obstructive jaundice, 463-464 Obstructive lung diseases, 190-191, 190f, 213-224. See also specific diseases. classification of, 213, 214f features of, 213, 214t, 246 future prospects for, 224b physical examination in, 194

Obstructive lung diseases (Continued) testing in, 195-197 flow-volume loops in, 208-209, 208f spirometry in, 207f, 208 Obstructive shock, 262, 263t Occipital lobe epilepsy, 1145 Occipital lobe lesions, 1069f, 1070t Occipital lobe seizures, 1144 Occipital lobe tumors, 1155 Occipital neuralgia, 1093 Occupational therapy, for rheumatoid arthritis, 827-828 Octreotide for acromegaly, 662-663 for dumping syndrome, 428 for insulinoma, 724 for thyrotropin-secreting pituitary tumors, 664 Oculoglandular fever, 920 Odynophagia, 408, 413 Older adults, 1196-1208. See also Aging. clinical care of, 1198-1205 atypical disease presentations in, 1200-1201, 1201t cognition in, 1201-1202, 1202t. See also Dementia. comorbid conditions in, 1199-1200 function and, 1199-1200 hearing in, 1203 incontinence in, 1203-1205, 1204t life expectancy and, 1199-1200, 1200f medications in, 1201 mobility in, 1203 mood in, 1202-1203 nutrition in, 1205 vision in, 1203 geriatric care for, 1196, 1206, 1208 high-risk circumstances for, 1206 care transitions, 1206 hospitalization, 1206 memory loss in, 1076 social and legal issues of, 1205-1206 advance directives, 1206 caregiving, 1205 finances, 1205-1206 mistreatment, 1205 systems of care for, 1206-1208 Oligodendroglioma, 1157 anaplastic, 1156 Oligomenorrhea, 740-742 Olivopontocerebellar atrophy, 1113-1114 Olsalazine, for inflammatory bowel disease, 436 Omega-3 fatty acids, 646 Omeprazole for peptic ulcer disease, 423-424 to prevent recurrent ulcer hemorrhage, 421-422 Onchocerca volvulus infection, 1040, 1040t Oncogenes, 11, 595, 595t in breast cancer, 610 lung cancer and, 266 Oncotic pressure, 305 Open reading frame, 3f Opening snap, 41-42, 42f Ophthalmoplegia, 1098, 1098t progressive external, 1187 Ophthalmoscopy, 1098 Opioids abuse of, 1225t-1228t, 1229 equianalgesic table for, 1214t for osteoarthritis pain, 872 overdose of, 1229 in palliative care, 1213, 1214t, 1216 in renal or hepatic insufficiency, 1213 in traumatic brain injury, 1137 withdrawal from, 1229 Opportunistic infections, 1028. See also Human immunodeficiency virus (HIV) infection, infections in. Opsoclonus-myoclonus, paraneoplastic, 619t Opsonization, 533 impaired, 1030 Optic atrophy, 1099 Optic neuritis, 1098-1099, 1169 Optic neuropathy ischemic, 1099 Leber hereditary, 1099 Oral cavity cancers of, 606 infections of, 946-950, 947t

Index Oral contraceptives, 737-738 blood pressure increase caused by, 183-184 for dysfunctional uterine bleeding, 741 ovarian cancer risk and, 612 systemic lupus erythematosus and, 839 venous thromboembolism secondary to, 584 Oral hairy leukoplakia, 1020 Oral rehydration, for infectious diarrhea, 983, 984t Oral ulcers and vesicles, 946-947, 947t in HIV-infected patients, 1021 in reactive arthritis, 831 in systemic lupus erythematosus, 835, 837t Organophosphate poisoning, 1193 Oriental cholangiohepatitis, 493 Orlistat, 395, 633, 705 Oropharyngeal cancers, 606 Orthopnea in cardiac disease, 33, 69-70 diaphragm paralysis with, 252-253 in respiratory disease, 192 Orthostatic hypotension diabetic neuropathy with, 718 in HIV-infected patients, 1025 hypoaldosteronism with, 683 Ortner syndrome, 88 Oseltamivir, 1035-1036 Osler nodes, in infective endocarditis, 962t Osler-Weber-Rendu syndrome, 566 Osmolality, 308-309, 309f Osmolar gap, 308 Osmolarity, urine, in acute kidney injury, 362t Osmotic diarrhea, 397t-398t, 398 Osmotic diuresis, 311 Osmotic equilibrium, 305 Osmotic gap, fecal, 393-394 in osmotic diarrhea, 398 in secretory diarrhea, 398 Osteitis fibrosa cystica, 785, 795-797, 796f-797f, 800 Osteoarthritis, 818, 819t, 870-872 Candida species causing, 986-987 Osteoarthropathy hypertrophic, 878 hypertrophic pulmonary, 194-195, 268t Osteoblasts, 774-775, 775f, 777-778, 780 Osteoclasts, 774-775, 775f, 777-778, 780, 782 Osteocytes, 774 Osteodystrophy Albright hereditary, 789 hepatic, 776 renal, 798-799, 799f, 882 transplant, 800 Osteogenesis imperfecta, 799-800 Osteoid, 774-775, 775f mineralization defects of, 797-799 Osteoid seams, 797-798, 798f Osteomalacia, 797-798, 798f anticonvulsants and, 790 hypophosphatemia and, 792 in primary biliary cirrhosis, 881 in renal osteodystrophy, 798-799 tumor-associated, 292, 792-793 vitamin D and, 789-790, 793, 798 Osteomyelitis, 987-988, 987t-988t fever associated with, 922 in sickle cell disease, 879, 988 Osteopenia definition of, 804-805, 805t glucocorticoid therapy causing, 863 Osteophytes, in osteoarthritis, 870-871 Osteoporosis, 802-810. See also Bone mineral density. in anorexia nervosa, 635-636 bone quality and, 802, 803f causes of, 802-804, 804t classification of, 804-805, 805t clinical manifestations of, 804 corticosteroid therapy causing, 827, 863 definition of, 802, 804-805, 805t diagnosis of, 804-805, 805f estrogen and, 743, 745, 802-804 fracture risk prediction tool, 805 future prospects for, 810b in hyperthyroidism, 882 investigational therapies for, 809 morbidity and mortality associated with, 802 prevention of, 805-807

Osteoporosis (Continued) in primary biliary cirrhosis, 881 risk factors for, 802 screening of women for, 734t systemic lupus erythematosus and, 839-840 transplant-related, 800 treatment of, 807-810, 808t work-up for secondary causes of, 804 Osteoporosis circumscripta, in Paget disease of bone, 813-814, 814f Osteoporosis-pseudoglioma syndrome, 799-800 Osteosarcoma, in pagetic lesion, 811-812 Ostium primum atrial septal defect, 75, 77 Ostium secundum atrial septal defect, 75, 77 Ebstein anomaly with, 79 Otitis externa, 945 malignant (necrotizing), 1161 Otitis media, 945 lateral sinus thrombosis secondary to, 1162 Otosclerosis, 1101 Oval fat bodies, 300, 302 Ovarian cancer, 612-613 Ovarian dysgerminoma, 1,25-dihydroxyvitamin D secretion by, 785 Ovarian teratoma, thyroid tissue in, 674-675 Overweight, 630-632 Ovine CRH test, 687 Ovulation, 732f, 733 Oxalate. See also Hyperoxaluria. soft tissue deposition of, 869 Oxcarbazepine, 1149-1150, 1150t in pregnancy, 1152 Oxycodone, 1214t Oxygen, ventilatory control and, 202-203, 203f Oxygen consumption, myocardial, 28-29 exercise and, 31 Oxygen free radicals, aging and, 1197 Oxygen supplementation adverse effects of, 261 in chronic obstructive pulmonary disease, 219 for cluster headache, 1090 Oxyhemoglobin dissociation curve, 204, 205f Oxytocin, 660, 667 P p53 tumor suppressor gene, 595-596, 624-625 P wave, 46-47, 47f PACE (Program of All-inclusive Care for the Elderly), 1207-1208 Pacemakers, artificial cardiac, 140, 140t-141t biventricular. See Resynchronization therapy. in hypertrophic cardiomyopathy, 152 Paclitaxel, 623t Paclitaxel-eluting stents, 104-105 Paget disease of bone, 811-816 clinical manifestations of, 811-812, 815t complications and associated conditions, 812, 814, 816 osteosarcoma as, 811-812 diagnostic evaluation of, 812-814, 814f-815f etiologic factors in, 811-812 future prospects for, 816b incidence and prevalence of, 811 pathology and pathophysiology of, 811-812, 813f treatment of, 814-816, 815t PAI-1. See Plasminogen activator inhibitor-1 (PAI-1). Pain abdominal. See Abdominal pain. of angina pectoris, 32-33, 33t, 99 vs. esophageal pain, 409 back, 1093-1095, 1094f, 1094t-1095t breast, 746-747 chest. See Chest pain. complex regional pain syndrome in, 1093 head. See Headache. muscle, 1182-1183 neck, 1093-1094, 1094f, 1094t neuropathic, 1178, 1178t in osteoarthritis, 871 pelvic in men, chronic, 758 in women, 747 on swallowing, 408

1267

Pain disorder, 1081-1082 Pain fibers, 382 Pain management for chest pain, in lung disease, 193 for diabetic neuropathy, 718 in osteoarthritis, 872 in palliative care, 1212-1213, 1214t, 1216 postoperative myocardial infarction and, 279-280 Palifermin, 627 Palliative cancer treatment, 622, 624, 627 Palliative care, 1210-1217 communicating and negotiating in, 1211-1212, 1211t ethical challenges in, 1216 feeding tube issues in, 1216 hospice in, 1215 key elements of, 1210 last hours and days in, 1216-1217 prognosis and, 1212 request for hastened death in, 1215-1216 requests for futile treatment in, 1216 spiritual distress in, 1215 subspecialty recognition for, 1217b symptom management in, 1212-1215, 1214t systems for, 1210 tests and interventions in, 1215 trajectories of illness and, 1210-1211 Palpitations, 33-34, 131 Pamidronate for hypercalcemia, 618, 618t for Paget disease of bone, 814-816, 815t Pancarditis, in rheumatic fever, 92 Pancoast tumors, 267 Pancreas anatomy of, 445, 446f development of, 445 gastronomas in, 426-427 physiology of, 445, 446f Pancreas divisum, 445, 450 Pancreatic abscess, 976t, 977 Pancreatic β-cell tumor, 724 Pancreatic cancer, 452-454, 453f, 607t, 609 Pancreatic cholera, 786 Pancreatic ducts endoscopy of, 402-403 magnetic resonance imaging of, 406 Pancreatic enzyme preparations, 452 Pancreatic fistula, 448, 451 Pancreatic function testing, 391 Pancreatic pseudocyst, 448, 451, 452f Pancreatic stone protein, 450-451 Pancreaticojejunostomy, lateral, 452 Pancreatitis abscess secondary to, 976t, 977 acute, 445-450 causes of, 445-446, 446t clinical course of, 445 clinical manifestations of, 447-448, 447f diagnosis of, 448 gallstones with, 446, 448, 450, 490-491, 490f, 493 incidence of, 445 pathogenesis of, 445-446, 447f severity assessment of, 448-450, 449f-450f, 449t treatment of, 450 calcific, of the tropics, 450 chronic, 445, 450-452, 450t, 452f biliary strictures secondary to, 493 hereditary, 451 hypocalcemia in, 447-448, 790-791 pancreas divisum and, 445, 450 triglyceride levels and, 645-646 Pancreatoscopy, 403 Pancytopenia, 498-499, 499t. See also Aplastic anemia. Panhypopituitarism, 692 Panic attacks, 1080, 1148 Panic disorder, 1080-1081 in fibromyalgia syndrome, 876 Panitumumab, 626t Pannus, 823, 825f Pantoprazole in gastrointestinal bleeding, 421-422 for peptic ulcer disease, 423-424 for stress bleeding prophylaxis, 418 in Zollinger-Ellison syndrome, 427

1268

Index

Papanicolaou (Pap) smear, 741-742 in adolescents, 735 in HIV-infected women, 1014-1015 Papaverine, penile injection of, 762 Papillary muscles anatomy of, 22 rupture of, 116 Papillitis, 1098-1099 Papules, 969, 971 Paracellin, 291-293, 293f-294f, 316 Paradoxical embolism atrial septal defect and, 76-77 stroke caused by, 1125 Parameningeal infections, 1160-1162 Paramyotonia congenita, 1186t, 1187 Paranasal sinuses. See Sinuses; Sinusitis. Paraneoplastic syndromes, 619-620, 619t. See also Hypercalcemia. in lung cancer, 267-268, 268t, 270 Parapneumonic effusion, 249-250, 256 Parasitic infections. See also Helminthic infections; Protozoal infections. of central nervous system, 942, 942f-943f Parasomnias, 1066-1067 Parasympathetic nervous system, cardiac impulses and, 118 Parathyroid adenoma, 785-786, 797 Parathyroid carcinoma, 785, 796-797 Parathyroid hormone, 775-776, 776f. See also Hyperparathyroidism. ectopic secretion of, 785 pulsatile secretion of, 782b renal actions of, 291-294, 297 calcium and, 773, 776 phosphate and, 776, 780-781, 782b subcutaneous for hypoparathyroidism, 789 for osteoporosis, 808t, 809 Parathyroid hormone–related protein, 784-785 hypophosphatemia and, 792 investigational use of, 809 from pheochromocytoma, 786 Parathyroidectomy hypocalcemia secondary to, 790 hypophosphatemia secondary to, 793 Paratonia, 1109 Paratyphoid fever, 912t, 913 Parenteral nutrition, 640-642, 641t. See also Total parenteral nutrition (TPN). hypercalcemia associated with, 787 in traumatic spinal cord injury, 1139-1140 Paresis, 1109 general, 939, 1001 Parietal lobe epilepsy, 1145 Parietal lobe lesions, 1069f, 1070, 1070t Parietal lobe seizures, 1144 Parietal lobe tumors, 1155 Parietal pleura, 248 Parkinson disease dementia of, 1075 drug-induced, 1113, 1113t future prospects for, 1117b idiopathic, 1109-1113, 1112t animal models of, 1114, 1117b SPECT imaging in, 1056-1057 tremor in, 1112, 1114 Parkinsonism toxic, 1114 vascular, 1114 Paronychia, 970 Paroxysmal hemicrania, 1090 Paroxysmal nocturnal dyspnea, 33, 69-70, 192 Paroxysmal nocturnal hemoglobinuria, 502-503, 528-529, 585 Partial thromboplastin time (PTT), 560, 562, 564-565, 565f, 565t in coagulation factor deficiencies, 576t Parvovirus B19 infection. See Mumps. Pasteurella multocida infection, of bite wounds, 988 Patent ductus arteriosus, 76f, 76t, 80 Patterson-Kelly syndrome, 412 Pauci-immune glomerulonephritis, 236, 324-325, 327 PCI. See Percutaneous coronary intervention (PCI). PCP (Pneumocystis carinii pneumonia). See Pneumocystis jiroveci pneumonia.

PCP (phencyclidine), 1225t-1228t, 1231-1232 PCR. See Polymerase chain reaction (PCR). Peak bone mass, 802, 804-805, 805t Peak expiratory flow (PEF), 208f Peak expiratory flow rate (PEFR), 208 Pedal spasm, 772, 788 PEEP. See Positive end-expiratory pressure (PEEP). Pegvisomant, for acromegaly, 662-663 Pelvic abscess, 976t, 977 Pelvic examination, in abdominal pain, 383 Pelvic inflammatory disease (PID), 1003-1005 Pelvic pain in men, chronic, 758 in women, 747 Pemphigus, oral lesions in, 947 Penetrance, 12 d-Penicillamine for systemic sclerosis, 848, 848t for Wilson disease, 652 Penicillin, hypersensitivity to, 905 Penile carcinoma, 765-766 Penile erection, mechanism of, 759, 760f Penile prosthesis, 762-763 Pentamidine, β-cell destruction by, 724 Pentazocine, scleroderma-like effects of, 847t Pentobarbital, to induce coma, 1137 Pentoxifylline for alcoholic liver disease, 471-472 in peripheral arterial disease, 166 Pepsin, 415-416 Pepsinogen, 415-416 Peptic ulcer disease, 419-421 chest pain in, 34t clinical presentation of, 420-421 complications of, 421-423 bleeding, 421-422, 423f gastric outlet obstruction, 423, 425 perforation, 422-423, 425 diagnosis of, 421 in dyspepsia revaluation, 425 epidemiology of, 419 NSAID-induced, 419-421 treatment and prophylaxis of, 424-425, 425t pathophysiologic factors in, 419-420, 420f tests for H. pylori in, 421, 422f treatment of, 423-426, 424t, 426f in Zollinger-Ellison syndrome, 419-420, 426-427 Percutaneous coronary intervention (PCI). See also Revascularization, coronary. in acute myocardial infarction, ST-segment elevation, 111-112 in cardiogenic shock, 115 after failed thrombolytic therapy, 112-113 in angina pectoris, 104-105 noncardiac surgery and, 277 in non–ST-segment elevation myocardial infarction, 110 in unstable angina, 110 Performance status, 622. See also Functional status. Pericardial effusion, 146 in effusive constrictive pericarditis, 148 in systemic lupus erythematosus, 835 Pericardial fluid, 145 diagnostic analysis of, 146 normal properties of, 22 therapeutic removal of, 146 Pericardial knock, 41, 42f, 147 Pericardial rub, auscultation of, 44, 145 Pericardial space, 145 Pericardial tamponade. See Tamponade, cardiac. Pericardial window, 146 Pericardiectomy for constrictive pericarditis, 148 for effusive constrictive pericarditis, 148 Pericardiocentesis, 146-148 Pericardiotomy, 146 Pericarditis acute, 145-146, 146t myocarditis with, 149 constrictive, 147-148, 148f vs. restrictive cardiomyopathies, 154, 154t in dialysis patients, 373 pain of, 33, 33t radiation-induced, 148 in rheumatic fever, 92

Pericarditis (Continued) rheumatoid arthritis with, 825-826 in systemic lupus erythematosus, 835, 837t traumatic, 157 Pericardium, 145 anatomy and physiology of, 22 trauma to, 157t, 158 tumors of, 156 Pericholangitis, inflammatory bowel disease with, 434 Perimenopause, 733, 742t Perinephric abscess, 976t, 990-991 Perineum, male, necrotizing infection of, 973 Periodic paralyses, 1187-1188 Periodontal infections, osteomyelitis in, 988 Peripartum cardiomyopathy, 151, 164 Peripheral arterial disease, 165-167, 166f, 166t erectile dysfunction in, 38, 165-166, 760-761 evaluation of, 38, 64-65, 165-166, 166t future prospects for, 186b Peripheral blood smear, 521-522, 522f Peripheral neuropathies, 1174. See also Plexopathies. classification of, 1171, 1172t, 1174, 1174t clinical features of, 1171, 1172t diabetic, 718, 881, 1180, 1190 mononeuropathies classification of, 1174-1175, 1174t common examples of, 1174-1175, 1175t, 1178-1179 multiple, 1174-1175 paraneoplastic, 619t polyneuropathies, 1175-1176 classification of, 1175-1176 clinical approach to, 1176-1177, 1177t differential diagnosis of, 1177t etiology of, 1176, 1176t hereditary, 1176t, 1177-1178, 1180-1181 laboratory approach to, 1177-1178, 1178t specific disorders, 1179-1181 symptomatic treatment of, 1178, 1178t Peritoneal dialysis, 375-376. See also Dialysis. peritonitis secondary to, 977-978, 978t Peritonitis, 977-978, 978t spontaneous bacterial, 479, 482-483, 977, 978t Pernicious anemia, 524-525 Peroneal neuropathy, 1175t, 1179 Persantine stress testing, 57-58 Persistent vegetative state, 1062-1063, 1062t Personality disorders, 1078t-1079t, 1082 Personalized medicine, 14b PET. See Positron emission tomography (PET). Petechiae, infective endocarditis with, 962t Petit mal, 1145-1146, 1145f Petit mal epilepsy, 1146 Petit mal status, 1151 Peutz-Jeghers syndrome, 442 P-glycoprotein, 624-625 pH acid-base assessment and, 317, 317t arterial blood, 316 esophageal, ambulatory monitoring of, 409-410 tubular fluid, 316-317, 317f urinary in acidosis, 299-300, 320 stone formation and, 342-343 Phagocytic cells, 892, 894-895 Phagocytosis of Mycobacterium tuberculosis, 896-897 by neutrophils, 533, 534f, 892 Pharmaceutical industry representatives, 19 Pharmacogenetics, 13 Pharmacogenomics, 11 Pharyngitis, 947-950, 948t fever and rash in, 915 glomerulonephritis secondary to, 325 group A streptococcal, 948 chorea secondary to, 1115 persistent or penicillin-unresponsive, 950 soft tissue infections secondary to, 949-950, 949t Pharynx, soft tissue infections in region of, 949-950, 949t Phencyclidine (PCP), 1225t-1228t, 1231-1232 Phenobarbital, 1149-1150, 1150t for status epilepticus, 1152t teratogenicity of, 1151-1152 Phenothiazines, for migraine, 1088

Index Phenoxybenzamine, for pheochromocytoma, unresectable, 178 Phentermine, 633, 705 Phentolamine, penile injection of, 762 d-Phenylalanine derivatives, 710t-713t, 714, 723 Phenytoin, 1150 in epilepsy, 1149-1150, 1150t for status epilepticus, 1152t teratogenicity of, 1151-1152 in traumatic brain injury, 1137-1138 Pheochromocytoma, 177t, 178, 689-690 hypercalcemia associated with, 786 in von Hippel-Lindau disease, 340 Philadelphia chromosome, 507, 511-512, 516-518, 625 Phlebitis. See also Thrombophlebitis. septic, catheter-related, 995 suppurative, 968 Phlegmon, 447-448 of floor of mouth, 950 parapharyngeal, 950 peritonsillar, 949 Phobias, 1080-1081 Phosphate chronic kidney disease and, 374, 374f deficiency of causes of, 780 manifestations of, 779, 782b fluid compartments and, 305, 306f homeostasis of, 778-781, 779f intestinal absorption of, 779f, 780 measurements of, 778 physiologic roles of, 778-779 renal handling of, 291-292, 779f, 780, 781f serum, 779 skeletal fluxes of, 778-780, 779f therapeutic preparations of, 778, 779t Phosphatonins, 781, 792-793 Phosphenes, 1099-1100 Phosphodiesterase type 5, 760f Phosphodiesterase type 5 inhibitors for erectile dysfunction, 762 vacuum device with, 762 for pulmonary arterial hypertension, 170 Photosensitivity, in systemic lupus erythematosus, 837-838, 837t Physical activity. See also Exercise. cancer risk and, 599 coronary artery disease and, 97 for weight loss, 632, 632t Physical therapy in osteoarthritis, 871-872 in rheumatoid arthritis, 827-828 in spondyloarthropathies, 832 in systemic sclerosis, 849 Pick disease, 1074-1075 Pickwickian syndrome, 246, 252 PID (pelvic inflammatory disease), 1003-1005 Pill esophagitis, 413 Pink puffer, 216 Pinworm, 1038-1039, 1040t Pioglitazone, 710t-713t, 712-713 Piperazines, 1232-1233 Pitting edema, 35 Pituitary gland anatomy and physiology of, 660, 661f future prospects for, 669b hormones of, 660, 661t. See also specific hormones. renal degradation of, 297 insufficiency of, 667, 667t posterior, 660, 667-669 screening tests for disorders of, 662t Pituitary tumors, 660-661, 662t ACTH-secreting, 662t, 664-666 gonadotropin-secreting, 662t, 666 growth hormone–secreting. See Acromegaly. prolactinoma, 660, 663 thyrotropin-secreting, 662t, 664 Plague, 920, 1044-1045, 1047-1048 Plain radiographs abdominal, 404, 405f in chronic pancreatitis, 451 in pain evaluation, 384 chest. See Chest radiography. in osteoarthritis, 871

Plain radiographs (Continued) of osteomyelitis, 987 in Paget disease of bone, 813-814, 814f Plant extracts. See Herbal supplements. Plasma, fresh frozen, 578 Plasma cell disorders, 550-554, 550t. See also Multiple myeloma. Plasma cells, 539, 540f Plasma compartment, 305, 306f Plasma exchange for hemolytic uremic syndrome, 587 for thrombotic thrombocytopenic purpura, 587 Plasmacytoma, 550-552, 550t Plasmapheresis in antiphospholipid antibody syndrome, 842-843 for Guillain-Barré syndrome, 1179-1180 for multiple sclerosis, 1167 for myasthenia gravis, 1192 for neuromyelitis optica, 1169 for vasculitis, ANCA-associated, 860 Plasmin, 559f, 562-563, 580-581 Plasminogen activator inhibitor-1 (PAI-1), 559f, 561-563, 580-581, 587 from adipose tissue, 631 Plasmodium, 889t, 915, 1039t. See also Malaria. Platelet count, 556-557. See also Thrombocytopenia; Thrombocytosis. reticulated, 566-568 Platelet Function Analyzer-100, 556-557, 564 Platelet refractoriness, 574 Platelet transfusion, 573-574 in acute renal failure, 573 in congenital platelet dysfunction, 573 contraindicated in thrombotic thrombocytopenic purpura, 587 for drug-induced bleeding, 572 failure of, 574 for immune thrombocytopenic purpura, 569 Platelets, 556-560. See also Antiplatelet therapy. activation of, 558, 560-563 bleeding associated with, 572-578, 572t bleeding time and, 556-557 circulating lifetime of, 556-557 development of, 498, 498f, 556-557 in diabetic patients, 719 procoagulant properties of, 556, 557t thrombosis associated with arterial, 581-582 laboratory evaluation of, 587 venous, 585-587 vessel wall interactions of, 555-559, 556f, 574 Plethysmography, 65 of lung volumes, 208 Pleura, 248 Pleural disease, 248-251. See also Pleural effusion; Pneumothorax. Pleural effusion, 248-249, 249t in asbestosis, 237-238 chest radiography of, 210, 248 complicated, 249-250, 256 future prospects for, 253b in heart failure, 35, 249 in lung cancer, 267-268 in lymphangioleiomyomatosis, 239 malignant, 250, 267-268 mesothelioma with, 250-251 parapneumonic, 249-250, 256 physical findings in, 196t pneumonia with fever and, 959 in systemic lupus erythematosus, 835 Pleural fluid, 248, 249t, 253b. See also Pleural effusion. pneumonia and, 959 Pleural rub, 195 Pleural space, 248 mesothelioma in, 250-251 Pleuritic chest pain, 193 in lung cancer, 267 Pleuritis, in systemic lupus erythematosus, 835, 837t Pleuropericardial rub, auscultation of, 44 Plexogenic pulmonary arteriopathy, 243-244 Plexopathies brachial, 1174 critical illness and, 1190 lumbosacral, 1174 Plummer-Vinson syndrome, 412

1269

PMI (point of maximal impulse), 39 Pneumococcal vaccine, 960, 960t for HIV-infected patient, 1016 for splenectomized patient, 1030 Pneumococcus. See Streptococcus pneumoniae infection. Pneumoconioses, 225-226, 228t-229t, 237-238 rheumatoid arthritis with, 825-826 Pneumocystis carinii. See Pneumocystis jiroveci pneumonia. Pneumocystis jiroveci, staining of, 898 Pneumocystis jiroveci pneumonia, 194, 257-258, 888, 953, 1023, 1024t glucocorticoid therapy and, 863 in HIV-negative immunocompromised hosts, 1031 prophylaxis against, 1019, 1019t, 1032-1033 Pneumocytes type I, 198 type II, 198 acute respiratory distress syndrome and, 262 Pneumonia, 254-258, 951-960 aspiration, 262, 951, 994 bacterial, 955-956, 958-959 Chlamydophila pneumoniae, 885, 956-957, 959t gram-negative, 956 Haemophilus influenzae, 255-256, 255t, 956, 959t Legionella, 957, 959t Mycoplasma pneumoniae, 255, 255t, 956, 959t Staphylococcus aureus, 255-256, 255t, 956, 959t Streptococcus pneumoniae, 254-256, 255t, 887, 955-956, 959, 959t tuberculous, 256-257, 256f, 951, 957-959, 959t chest radiography in, 254-255, 953, 953t with Pneumocystis jiroveci, 257, 953 clinical presentation of, 254 community-acquired, 254-255, 255t risk stratification in, 953-954, 954t, 958 complications of, 256 definition of, 254 diagnosis of, 953-954 differential diagnosis of, 952-953 laboratory findings in, 953 radiographic patterns in, 953, 953t empyema in, 959 endobronchial obstruction in, 959 eosinophilic, 239 epidemiology of, 190, 254, 951-952 associated disorders, 951-952, 952t associated exposures, 951-952, 952t population groups, 951-952, 952t future prospects for, 258b in HIV-infected patients, 1023-1024, 1024t hospital-acquired, 255 incorrect diagnosis or treatment of, 959 interstitial. See Interstitial pneumonias. necrotizing, 953-954, 953t, 955t nosocomial, 255-256, 255t, 994-995, 994f gram-negative bacilli in, 956, 994 pathogenesis of, 951 pathogens causing, 254, 255t, 951-952, 952t with pleural effusion, 249-250 and fever, 959 with pleurisy, chest pain in, 34t Pneumocystis. See Pneumocystis jiroveci pneumonia. prevention of, 960, 960t routes of spread in body, 254, 951 treatment of, 254, 958-959. See also specific organism. in community-acquired infection, 255, 957, 958t empirical, 954, 957, 958t in nosocomial infection, 255-256 targeted initial therapy, 958-959, 959t ventilator-associated, 255, 994-995 viral, 954-955 Pneumonitis, definition of, 254 Pneumothorax, 250 catamenial, 250 in lymphangioleiomyomatosis, 239 physical findings in, 196t spontaneous, 250 chest pain in, 34t tension, 250 Podagra, 865-866 Podocytes, 288-289, 288f-289f, 323 in minimal change disease, 327-328 Podofilox, 1006 Poikilodermatous eruption, 851

1270

Index

Point mutations, 7, 7t Point of maximal impulse (PMI), 39 Poiseuille’s law, 29 Poisoning. See also Toxins. drug overdoses, 264t, 265 toxic gases, 264-265, 264t Poliovirus vaccine, 1034-1035 Poly A tail, 3, 5 Polyarteritis nodosa, 859f, 860-861 leukocytoclastic changes in, 862 renal involvement in, 350, 860-861 Polycystic kidney disease autosomal dominant, 337-338 autosomal recessive, 338-339 investigational agent for, 344b Polycystic liver disease, 338 Polycystic ovary syndrome, 736, 740-741, 746 Polycythemia vera, 507-509, 508t, 585-586 Polydipsia, primary, 668 Polygenic disorders, 11-12, 11t Polyglandular autoimmune syndrome type I, 681 Polyglandular autoimmune syndrome type II, 675, 681 Polymerase chain reaction (PCR), 10-11 clinical uses of, 900, 901f, 902t Polymorphisms, genetic, 7-8 Polymorphonuclear leukocytes. See Neutrophils. Polymyalgia rheumatica, 862 fever associated with, 922 with giant cell arteritis, 169, 862, 922, 1092 Polymyositis, 1188-1189, 1189t. See also Myositis, idiopathic. Polysomnography, 246, 1064-1066, 1065f Porphyria cutanea tarda, 655f, 656-657, 656t Porphyrias, 654-657, 655f, 656t drug-precipitated, 654, 655t, 656-657 Portal hypertension, 478-480, 480t ascites and, 481-482 in Budd-Chiari syndrome, 486 portal vein thrombosis with, 485-486 Portal triad, 489f Portal vein thrombosis, 485-486 Port-wine stain, facial, 1121 Positive end-expiratory pressure (PEEP), 260-261 in acute respiratory distress syndrome, 262 alveolar pressure and, 203-204 Positive predictive value, 600 Positive pressure ventilation, noninvasive. See also Continuous positive airway pressure (CPAP). in amyotrophic lateral sclerosis, 1172-1173 in chronic obstructive pulmonary disease, 219 Positron emission tomography (PET) intracranial imaging with, 1057 of brain tumors, 1155 before epilepsy surgery, 1148 in lung disorders, 197, 211 cancer, 211, 268 myocardial perfusion imaging with, 58, 59f in sarcoidosis, 232 of solitary pulmonary nodule, 270 Postanginal sepsis, 949 Postconcussive syndrome, 1138 Posterior cerebral artery, stroke associated with, 1127, 1127t Posthepatic jaundice, 463-464 Postherpetic neuralgia, 917, 971, 1093 Postictal phase, 1142-1144 Postictal state, 1058, 1061 Postoperative care. See Surgery, noncardiac. Postpartum care, 739-740 interpersonal violence and, 748 Postpartum depression, 739 Postpartum hemolytic uremic syndrome, 368 Postpartum psychosis, 739 Postpartum thyroiditis, 674, 739-740 Postpharyngitic hematuria, 325 Postrenal azotemia, 302, 359, 360f evaluation of, 362 Poststreptococcal glomerulonephritis, 324-325, 325t Post-test probability, 17 Post-thrombotic syndrome, upper extremity, 171 Post-transplantation lymphoproliferative disorder, 553 Post-traumatic epilepsy, 1145 Post-traumatic stress disorder, 1080-1081 in women, 730-731, 748 Postvoid residual urine, in men, 753-754

Potassium, 312-314. See also Hyperkalemia; Hypokalemia. fluid compartments and, 305, 306f renal secretion of, 294-296 Potassium channelopathy, 1186t Potassium hydroxide (KOH) preparation, 888, 898 PPD. See Purified protein derivative (PPD) test. PR interval, 46-47, 47f Pramlintide, 710t-713t, 714 Prealbumin, protein status and, 638-639 Preconception care, 736-737 Precordium, examination of, 38-39 in heart failure, 70 Prediabetes, 698, 700 Prednisone. See also Corticosteroid therapy. for autoimmune hemolytic anemia, 527 for idiopathic inflammatory myositis, 853-854 for immune thrombocytopenic purpura, 569 for inflammatory bowel disease, 436 for myasthenia gravis, 1192 for temporal arteritis, 1092 Preeclampsia, 184, 351-352 acute kidney injury in, 368 antihypertensive medications in, 352, 352t glomerular endothelium and, 289 microangiopathic hemolysis caused by, 528 risk factors for, 351-352, 351t thrombocytopenia in, 571 Preexcitation, 129 Preexcited tachycardias, 124 Pregabalin, 1149-1150, 1150t Pregnancy acute kidney injury of, 367-368 alcohol consumption in, 1224 anticoagulation in, 590 antiepileptic drugs in, 739, 739t, 1151-1152 antihypertensive agents in, 352, 352t antiphospholipid antibody syndrome and, 590, 841-843, 842t cardiovascular adaptations to, 162 with cardiovascular disease, 162 aortic stenosis, 163 arising during pregnancy, 163-164 congenital heart disease, 163 Marfan syndrome, 163 mitral stenosis, 162-163 prosthetic valves, 163 chronic kidney disease and, 374 in diabetic patients, 706. See also Gestational diabetes mellitus. epilepsy and, 1151-1152 herpes simplex virus infection in, 1000 history of complications in, 739 HIV infection in, 1009, 1014, 1017, 1026 HIV testing in, 1013 hypertension in, 163, 184, 351-352, 352t follow-up care with, 739 with thrombocytopenia, 571 hyperventilation in, 246 interpersonal violence during, 748 prescribing medication in, 738-739, 738t-739t preventive health recommendations during, 734t systemic lupus erythematosus and, 838-839 travel during, 1036-1037 venous thromboembolism in, 584 von Willebrand disease and, 574-575 Pregnancy loss, in antiphospholipid antibody syndrome, 841-843, 842t, 843b Prehepatic jaundice, 461t, 462 Prehypertension, 174, 175t Preload, 27-28, 28t Premature beats, 120-122, 121f Premature infants, respiratory distress syndrome in, 189 Preoperative care. See Surgery, noncardiac. Prerenal azotemia, 302, 359-360, 360f diagnostic evaluation in, 361-362, 362t Presbycusis, 1101 Pressure palsies, hereditary neuropathy with liability to, 1174 Pressure sores, 971, 988, 1140, 1206 Pressure support ventilation, 260-262 Pressures, intracardiac, measurement of, 58-59, 60f. See also Filling pressures. right atrial, 60, 62t

Presyncope, 133 Pre-test probability, 17 Pretibial myxedema, 672-673, 882 Primaquine for malaria, 1037 for malaria prophylaxis, 1035-1036 Primary biliary cirrhosis, 463-464, 881 Primary chemotherapy, 624 Primary ciliary dyskinesia, bronchiectasis in, 220 Primary lateral sclerosis, 1173 Primary miRNA (primiRNA), 5 Primary research studies, 16-17, 17t Primary sclerosing cholangitis, 493, 493f, 494b cholangiocarcinoma and, 493-494, 494b colon cancer risk and, 432 inflammatory bowel disease with, 435, 493 jaundice in, 464 Primidone, 1149-1150 teratogenicity of, 1151-1152 Primitive neuroectodermal tumor, 1157 Principal cells, renal, 293-294 tubular acidosis syndromes and, 320 Prinzmetal angina. See Variant (Prinzmetal) angina. Prion diseases, 884-885, 1075, 1163-1164, 1163f Probenecid, for gout, 868, 868t Probiotics, for inflammatory bowel disease, 437 Procainamide, lupus caused by, 234, 235t Procalcitonin, serum, in pneumonia, 953 Proctocolitis, in men who have sex with men, 1006-1007 Progesterone, menstrual cycle and, 732f, 733 Progesterone challenge, 740 Progressive external ophthalmoplegia, 1187 Progressive massive fibrosis, 237 Progressive multifocal leukoencephalopathy, 943-944, 943t in HIV-infected patients, 1022, 1023t natalizumab associated with, 1167-1169 Progressive muscular atrophy, 1173 Progressive supranuclear palsy, 1113 Prolactin, 660, 661t, 663 male hypogonadism caused by, 692 Prolactinoma, 660, 663 Prolonged pulmonary eosinophilia, 239 Promoter sites, 3f, 5-6 disease phenotype and, 12 Propofol, to induce coma, 1137 Prostacyclin as coronary vasodilator, 29 COX-2 inhibitors and, 559 for pulmonary hypertension, 170, 243-244 Prostacyclin analogues in Buerger disease, 169 for digital ulcerations, 847, 848t for pulmonary arterial hypertension, 170 Prostaglandin analogues, peptic ulcer disease and, 424-425 Prostaglandin E1 penile injection of, 762 penile insertion of, 762 Prostaglandin E2, fever and, 910-911 Prostaglandins biosynthesis of, 417, 417f gastric mucosa and, 417, 419-420, 424-425 glomerular filtration rate and, 305-306 renal transport and, 292-294, 293f water reabsorption, 296 Prostate cancer, 611t, 763-765 autopsy incidence vs. clinical detection, 763 vs. benign hyperplasia, 754 diagnosis of, 763-764 risk factors for, 763, 763t screening for, 763-764 treatment of for advanced disease, 626-627, 765, 765t for localized disease, 764-765, 764t Prostate gland abscess of, 757, 922, 991 biopsy of, 764-765 symptom index related to, 753 zonal anatomy of, 753f Prostate-specific antigen (PSA), 753-754, 763-765 causes of increase in, 763-764, 764t LHRH analogues and, 765 5α-reductase inhibitors and, 755

Index Prostatic hyperplasia, benign (BPN), 752-756, 756t Prostatic hypertrophy, 336 Prostatic secretions, expressed, 757-758 Prostatitis, 757-759, 991 vs. benign prostatic hyperplasia, 754 Prostatodynia, 758 Prosthetic heart valves, 92-93, 92f-93f auscultation with, 44-45 infective endocarditis of, 961, 966 microorganisms in, 964t prophylaxis of, 93-94 noncardiac surgery in patient with, 281 pregnancy in patient with, 163 surgical placement of, 159-160 Protein dietary requirements for, 639, 639t dietary restriction of, in chronic kidney disease, 371, 371t digestion and absorption of, 389 fluid compartments and, 305, 306f renal barriers to, 323 Protein C. See also Activated protein C. assay for, 587 deficiency of, 582t, 583-584 in heparin-induced thrombocytopenia, 586 Protein S assay for, 587 deficiency of, 582t, 583-584 Protein synthesis. See Translation. Proteinase-3, antibodies against, 235-236, 327, 860 Proteinuria, 300 annual screening for, in diabetic patients, 370-371, 717 measurement of, 300 in nephrotic syndrome, 301t, 302 podocytes and, 288-289 in preeclampsia, 351 selective, 327-328 therapy of, in glomerular disease, 325 Proteomics, 13 Proteus species, 886 Prothrombin G20210A, 582t, 583, 585, 587 Prothrombin complex concentrate, 578 Prothrombin time (PT), 560-562, 564, 565f, 565t in coagulation factor deficiencies, 576t liver function and, 456, 457t, 577 in alcoholic hepatitis, 471 biopsy and, 458-459 in cirrhosis, 458 Prothrombotic disease states, 584t, 585 Proton pump (H+,K+-ATPase), 415-416, 415f Proton pump inhibitors for gastroesophageal reflux disease, 410, 412 in gastrointestinal bleeding, 387-388, 421-422 for peptic ulcer disease, 423-425 for stress bleeding prophylaxis, 418 in Zollinger-Ellison syndrome, 427 Proto-oncogenes, lung cancer and, 266. See also Oncogenes. Protozoal infections. See also specific organisms and infections. diarrhea in, 982 in HIV-infected patients, 1024-1025, 1025t organisms causing, 889, 889t in travelers and immigrants, 1038, 1039t in United States, 1038, 1039t Proximal tubule acidosis associated with, 319, 319f, 319t functions of, 291-292, 291f in acid-base balance, 316-317, 317f vitamin D and, 297 waste excretion, 296 magnesium wasting and, 794 structure of, 286-290, 287f-288f PSA. See Prostate-specific antigen (PSA). Pseudobulbar affect, 1172 Pseudofractures, 797-798, 799f Pseudogout. See Calcium pyrophosphate deposition disease (pseudogout). Pseudohermaphroditism, male, 691, 693 Pseudohypoaldosteronism, 320-321 Pseudohypoparathyroidism, 788t, 789 Pseudoinfarction, 53

Pseudomonas aeruginosa infection cutaneous, 970 otitis externa, 945, 1161 pulmonary, 956 Pseudo–Pelger-Huët anomaly, 503, 522f Pseudo-pseudoseizures, 1144 Pseudoseizures, 1148 Pseudotumor cerebri. See Intracranial hypertension, idiopathic. Pseudoxanthoma elasticum, 566 Psoas abscess, 976t Psoriasis, in HIV-infected patients, 1020t Psoriatic arthritis, 829-832, 830t Psychiatric disorders, 1077-1082 of anxiety, 1079t-1080t, 1080-1081 in epilepsy, 1152-1153 in older adults, 1202-1203 causes of, 1077, 1078t classification of, 1077, 1078t-1079t definition of, 1077 future prospects for, 1082b of mood, 1077-1080, 1078t-1079t. See also Depression. of personality, 1078t-1079t, 1082 psychotic, 1078t-1079t, 1081 somatoform, 1078t-1079t, 1081-1082 syndromes present in, 1077, 1078t Psychomotor seizures, 1143 Psychotic disorders, 1078t-1079t, 1081 PT. See Prothrombin time (PT). Ptosis, 1097 in mitochondrial disease, 1187 PTT. See Partial thromboplastin time (PTT). Pubertal growth spurt, 691 Puestow procedure, 452 Pulmonary alveolar proteinosis, 240 Pulmonary artery gas exchange and, 198-199 Takayasu arteritis of, 169 Pulmonary artery catheter, 60, 61f differential diagnosis with, 62t hemodynamic measurements with, 263t infection control with, 996t intraoperative, 280 in shock, 263, 263t Pulmonary artery pressure exercise and, 198-199 factors affecting, 241 measurement of, 60, 61f Pulmonary capillary wedge pressure, 26-27, 27t, 58-59 in heart failure, 71 as measure of preload, 27-28 measurement of, 60, 61f, 62t in myocardial infarction, acute, 114-115 noninvasive estimation of, 71 in pulmonary arterial hypertension, 170 in shock, 263t Pulmonary circulation exercise and, 31 physiology of, 30, 198-199, 203-204, 203f Pulmonary congestion mitral stenosis with, 88-89, 88f myocardial infarction with, 114 Pulmonary disorders. See Respiratory disorders. Pulmonary edema in acute coronary syndrome, 106 in acute respiratory distress syndrome, 262 in cardiac disease, 35 in heart failure acute onset of, 67 vs. adult respiratory distress syndrome, 71 chest radiograph of, 70, 70f diuretics and, 72 after myocardial infarction, 114 pathophysiology of, 68, 69f noncardiogenic, 262 Pulmonary embolism, 171-173, 172f-173f, 241-243. See also Venous thromboembolism. chest pain of, 33, 34t clinical presentation of, 241-242 dyspnea in, 33 epidemiology of, 241 evaluation of, 242-243, 242f, 243t management of, 243, 587-590, 589t obstructive shock secondary to, 262

1271

Pulmonary embolism (Continued) pathophysiology of, 241 in pregnancy, 590 risk factors for acquired, 584-585 inherited, 582-584 septic infective endocarditis with, 962, 966 jugular vein thrombophlebitis with, 949 syncope in, 34-35 Pulmonary fibrosis idiopathic, 190-191, 226-227, 227f, 228t-229t, 230 chest radiography in, 227f, 230 computed tomography in, 230, 230f future prospects for, 240b lung compliance in, 201, 201f physical findings in, 196t in spondyloarthropathies, 831 Pulmonary function testing, 195-197, 206-209, 207f-208f in chronic obstructive pulmonary disease, 216-217 indications for, 206-207, 207t in interstitial lung disease, 226 patterns observed in, 190-191, 195-197, 208-209 preoperative, in lung cancer, 270-271 Pulmonary hemorrhage diffuse alveolar, 235-237 idiopathic, 237 in systemic lupus erythematosus, 835 Pulmonary hypertension, 170 arterial, 170 familial, 243 idiopathic, 243-244 chest pain in, 34t, 193 in chronic obstructive pulmonary disease, 216-217 classification of, 170t, 241, 242t in connective tissue disorders, 233 definition of, 170, 241 delayed manifestations of, 241 in Eisenmenger syndrome, 82 future prospects for, 244b mitral regurgitation with, 90 noncardiac surgery in patient with, 282 obesity and, 252 pulmonic regurgitation secondary to, 91 secondary, 242t, 244 sleep apnea with, 245-246 in systemic sclerosis, 845-849, 846t, 848t Pulmonary infarction, 241-242 vs. pneumonia, 959 Pulmonary infiltrates, in immunocompromised patients, 1031, 1032f Pulmonary rehabilitation programs, 219 Pulmonary vascular diseases, 190-191, 190f, 241-244. See also Cor pulmonale; Pulmonary embolism; Pulmonary hypertension. Pulmonary vascular resistance, 30, 198-199 Pulmonary vasculitis, 235-237 Pulmonary venous congestion, chest x-ray in, 46 Pulmonary-renal syndrome, 236, 323-324, 327 Pulmonic regurgitation, 91 Pulmonic stenosis, 78t, 79, 91 in tetralogy of Fallot, 81 Pulmonic valve, anatomy of, 22 Pulmonic veins, 198-199 Pulse oximetry, 195-197, 209 Pulse pressure, aging and, 182-183, 183f Pulses, arterial, 36-38, 38f Pulsus alternans, 36-38, 38f Pulsus bisferiens, in hypertrophic cardiomyopathy, 152 Pulsus paradoxus, 36-38, 38f in asthma, severe, 194, 223 in cardiac tamponade, 147 Pulsus parvus et tardus, in cardiac tamponade, 36-38, 38f Pupillary reactivity, in coma, 1059f, 1061-1062, 1062t Pupils examination of, 1096-1097, 1098f intracerebral hemorrhage and, 1133t Purified protein derivative (PPD) test, 257, 257t. See also Tuberculin testing. in HIV-infected patient, 1016 Purkinje fibers, 24, 24f

1272

Index

Purpura. See also Thrombotic thrombocytopenic purpura. Henoch-Schönlein, 237, 329-330, 566, 859f, 860 leukocytoclastic vasculitis in, 862 immune thrombocytopenic, 568-569 maternal, 570 in meningococcal infection, 935 palpable, 566 post-transfusion, 570 senile, 565-566 vascular, 565-566 Purpura fulminans, neonatal, 583-584 Pustules, 969-970, 970t Pyelonephritis, 989-991 in pregnancy, 368 Pyloric sphincter, 414, 415f Pyoderma gangrenosum, inflammatory bowel disease with, 435 Pyomyositis, 973 Pyramidal system, 1109 Pyridostigmine, for myasthenia gravis, 1192 Pyridoxine (vitamin B6), peripheral neuropathy caused by, 1177 Pyrophosphate arthropathy, chronic, 869 Pyropoikilocytosis, hereditary, 528, 528t Pyuria, 300, 989-990 sterile, 991 Q Q fever, 912t, 913-914 Q waves, 47, 47f pathologic, 53 in nonischemic cardiac disease, 53 ventricular aneurysm with, 51-53 QRS alternans, 146 QRS complex, 46-47, 47f limb leads and, 47-48, 48f QT interval, 47, 47f metabolic and drug influences on, 53, 54f prolongation of, 143, 143t in Gitelman syndrome, 315 Quadrantopia, 1096, 1097f Quality of life, 19-20 Quinidine, for malaria, 1037 Quinine, insulin excess caused by, 724 Quinsy, 949 Q-wave myocardial infarction. See Myocardial infarction, ST-segment elevation (STEMI). R R prime (R′), 47 R wave, 47, 47f, 49 Rabeprazole, for peptic ulcer disease, 423-424 Rabies, 941 Rachitic rosary, 797-798 Radiation exposure interstitial lung disease and, 228t-229t from terrorist weapons, 1046t, 1049 Radiation nephritis, 335-336 Radiation therapy, 622 acute effects of, 622, 623t for brain tumors, 1156 lymphoma, 1157 metastatic, 1157 late effects of, 619t, 620, 622, 623t for meningioma, 1157 for prostate cancer, 764-765 for spinal cord compression, 617 for spinal cord tumors, 1157-1158 Radiculopathy cervical, 1093-1094, 1094t lumbar, 1094-1095, 1095t lumbosacral, in diabetes mellitus, 1180 Radiofrequency ablation. See Catheter ablation, radiofrequency. Radiographs. See Plain radiographs. Radionuclide imaging bone scan, in Paget disease of bone, 813-814, 815f cardiac, 55-58, 59f. See also Nuclear myocardial perfusion imaging. gallbladder, 407, 492

Radionuclide imaging (Continued) gastrointestinal, 388, 406-407 gastric-emptying scan, 428 of gastrinoma, 427 hepatobiliary scan, 407, 492 renal, 303, 303t in renal artery stenosis, 347 thyroid, 671 Radionuclide ventriculography, 57 Radon, lung cancer and, 266, 603 Ragged red muscle fibers, 1187 Raloxifene, for osteoporosis, 808-809, 808t Ramipril, for hypertension, 179t-180t, 180 Ramsay Hunt syndrome, 970-971, 1093 Randomized controlled trials, 16-18 Range of motion, assessment of, 874 Ranitidine, for peptic ulcer disease, 423-424 Ranolazine, for angina pectoris, 103, 103t Rapamycin. See Sirolimus (rapamycin). Rape, 748 Rapid urease test, 421 Rapidly progressive glomerulonephritis (RPGN), 302, 323-324, 324t, 325f in ANCA-associated vasculitis, 327 in antiglomerular basement membrane disease, 327 crescent formation in, 323-327, 323f microscopic polyangiitis with, 236 subacute bacterial endocarditis with, 326 Rapidly progressive renal failure, 301t-302t, 302 Rasagiline, 1112, 1112t Rasburicase, 367, 514-515 Rash. See also Skin lesions. of dermatomyositis, 1188-1189 febrile syndromes with, 915-917, 915t in returning traveler, 1038 Rat-bite fever, 885 Raymond syndrome, 1126 Raynaud disease, 846-847 Raynaud phenomenon, 169 in polymyositis/dermatomyositis, 851 in Sjögren syndrome, 855 in systemic lupus erythematosus, 835, 837-838 in systemic sclerosis, 845, 846t, 847-848, 848t RBCs. See Red blood cells (RBCs, erythrocytes). RCRI. See Revised cardiac risk index (RCRI). Reactive arthritis, 819t, 829 clinical features of, 830-833, 830t epidemiology of, 829 pathogenesis and pathophysiology of, 829-830 radiographic features of, 831-832 treatment of, 832-833 Recessive mutation, 11t, 12 Recombination, genetic, 8-9, 9f Rectal examination (DRE) in abdominal pain, 383 in gastrointestinal bleeding, 387 for male urinary symptoms, 753-754 in prostate cancer, 763-764 in prostatitis acute bacterial, 757 chronic bacterial, 757 Red blood cell casts, 300-301, 301t Red blood cell scan, in gastrointestinal bleeding, 388, 406-407 Red blood cell transfusion, in sepsis, 930 Red blood cells (RBCs, erythrocytes) carbonic anhydrase in, 204 normal structure and function of, 520 progenitors of, 497-498, 498f 5α-Reductase, 752 5α-Reductase deficiency, 693 5α-Reductase inhibitors, for benign prostatic hyperplasia, 754-755, 756t Reed-Sternberg cell, 546 Reentry, 119-120, 120f Refeeding syndrome, 641-642 Reflex seizures, 1144, 1146 Reflex sympathetic dystrophy, 1093 Reflexes, in neuromuscular diseases, 1172t Refractory period, of cardiac cell, 118 Refsum disease, 1176t Regenerative medicine, 13-14 Rehabilitation, cardiac after acute coronary syndrome, 116-117 in heart failure, 72

Reiter syndrome, 829, 831. See also Reactive arthritis. Relative risk reduction, 18 Remodeling, cardiac, in heart failure, 68-69, 68f Renal. See also Kidney(s). Renal arteries anatomy of, 286, 287f, 345, 346f aortic dissection and, 348-350 Renal artery stenosis atherosclerotic, 177, 178f, 346-348, 347f clinical evaluation for, 346-347, 347t in fibromuscular dysplasia, 348, 348t, 349f hypertension secondary to, 177, 178f, 345-352 revascularization for, 348t pathophysiology of, 345-352, 346f in Takayasu arteritis, 350 Renal azotemia, 302, 359, 360f Renal biopsy, 303-304, 303t, 324-325 in acute kidney injury, 362-363 in chronic kidney disease, 369 of cystic masses, 337 Renal blood flow, 290 Renal cell carcinoma, 339-340, 611t, 612 acquired cystic kidney disease and, 339 renal vein thrombosis in, 356 in von Hippel-Lindau disease, 340, 612 Renal corpuscle. See Glomerulus (renal corpuscle). Renal crisis, in scleroderma, 846-848, 846t, 848t Renal cysts, 336-337, 337t in tuberous sclerosis, 340 Renal failure. See also Renal insufficiency. acute, 301t, 302. See also Acute kidney injury (AKI). definitions of, 302, 359 hypercalcemia in, 787 in multiple myeloma, 552 chronic. See also Chronic kidney disease (CKD). anemia of, 526 definition of, 370t fibroblast growth factor 23 in, 292 hypercalcemia in, 785-787 gadolinium toxicity in, 847 in hepatorenal syndrome, 483 in HIV-infected patients, 1026 hypermagnesemia in, 793 hyperphosphatemia secondary to, 791-792 hypoglycemia in, 724 metabolic acidosis in, 318 myoglobinuria and, 1190 protein dose in, 639, 639t rapidly progressive, 301t-302t, 302 in liver disease, 483 Renal failure index, 362t Renal function tests, 298-300, 299t-300t Renal insufficiency chronic, hyperkalemia in, 312-313 in HIV-infected patients, 1026 hypertension secondary to, 177, 184 hypocalcemia in, 789 myoglobinuria and, 1190 revascularization for, 348t in sepsis syndrome, 929 surgical risk and, 274-276, 275t Renal osteodystrophy, 798-799, 799f, 882 Renal replacement therapies, 375-379. See also Dialysis; Kidney transplantation. Renal tubular acidosis, 319, 319f-320f, 319t urinary pH in, 299-300, 320 Renal tumors, 339-340 Renal veins anatomy of, 345 catheterization of, 303 thrombosis or occlusion of, 356-357, 357f Renin adrenal insufficiency and, 682-683 function of, 30, 679-680 juxtaglomerular apparatus and, 289, 297, 679-680 mineralocorticoid deficiency and, 683 plasma level of in Gitelman syndrome, 315 in hyperkalemic renal tubular acidosis, 320 in renal artery stenosis, 345-346 Renin-angiotensin-aldosterone system, 679-680, 681f blood volume and, 30 in chronic kidney disease, 369-370 in heart failure, 68f, 69-70 diuretics and, 72

Index Renin-angiotensin-aldosterone system (Continued) hypertension and, 297 hyporeninemic hypoaldosteronism and, 312-313, 320, 683 Renovascular disease, 345-352 Renovascular hypertension, 166-167, 177, 177t, 345-352. See also Renal artery stenosis. Repaglinide, 710t-713t, 714 Reperfusion therapy. See Percutaneous coronary intervention (PCI); Thrombolytic therapy. Reptilase time, 575-578 Research studies evaluating, 18 quality of life as outcome in, 19 types of, 16-17, 17t Residual volume (RV), 207-208, 207f Resistance vessels, 29 Respiratory acidosis, 321-322 Respiratory alkalosis, 322 Respiratory bronchiolitis–associated interstitial pneumonia, 225, 227-230, 228t-229t Respiratory burst, 533 Respiratory control brainstem in, 202-203 disorders of, 190-191, 190f, 245-247. See also Sleep apnea. Respiratory disorders, 189-191. See also Interstitial lung diseases; Obstructive lung diseases. in children, 189 classification of, 190-191, 190f evaluation of. See Respiratory evaluation. future prospects for, 191b, 197b major causes of death and disability, 189-190 Respiratory distress. See Adult respiratory distress syndrome (ARDS); Infant respiratory distress syndrome. Respiratory evaluation, 192-197 history in, 192, 194 physical examination in, 194-195, 194t, 196t lung cancer and, 267 symptoms in, 192-193, 193t testing in, 195-197. See also Pulmonary function testing. arterial blood gases, 209, 209t bronchoprovocation testing, 209, 209f bronchoscopy, 211 diffusion capacity, 209 future prospects for, 211b imaging modalities, 210-211 Respiratory failure acute, 259-260 in kyphoscoliosis, 251-252 Respiratory muscles, 188, 200 Respiratory physiology, 198-206 gas exchange in, 199, 204, 204f-205f abnormalities of, 204-206, 205f-207f pulmonary anatomy and, 198-199 mechanics of, 200-202, 200f-202f, 251 perfusion in, 203-204, 203f ventilation in, 199-200, 200f control of, 202-203, 203f distribution of, 202, 202f Respiratory rate. See Breathing frequency. Respiratory syncytial virus (RSV) infection, 219 Respiratory system, 188 Response elements, 5 Restless legs syndrome, 1067 Restraints, in confused older adults, 1202 Restriction fragment length polymorphisms (RFLPs), 9 Restrictive cardiomyopathies, 149, 150t, 153-154 vs. constrictive pericarditis, 154, 154t Restrictive lung diseases, 190-191, 190f. See also Interstitial lung diseases. physical examination in, 194 testing in, 195-197, 208 flow-volume loops in, 208-209, 208f Resynchronization therapy, 68, 73-74 in dilated cardiomyopathy, 151 Reteplase (r-PA), 112, 112t Reticulated platelet count, 566-568 Reticulocyte count, 521 Retinal artery, stroke affecting, 1126-1127 Retinal examination, kidney disease and, 298 cis-Retinoic acid, hypercalcemia caused by, 786

all-trans-Retinoic acid (tretinoin), for acute promyelocytic leukemia, 517, 626t Retinopathy diabetic, 717-718 hypertensive, 184-185, 184f Retrobulbar neuritis, 1098-1099 Retrograde pyelography, 303 Retroperitoneal abscess, 976t, 977 Retropharyngeal space abscess, 949-950 Rett syndrome, 1120 Revascularization, coronary. See also Coronary artery bypass grafting (CABG); Percutaneous coronary intervention (PCI). in angina pectoris, 104-105 antiplatelet agents in, 581-582 after myocardial infarction, 111-112 in cardiogenic shock, 115 noncardiac surgery and, 276-277, 278f in non–ST-segment elevation myocardial infarction, 110 transmyocardial laser, 105 in unstable angina, 110 Revascularization, peripheral, 165-167, 166f Revascularization, renal artery, 177, 347-348, 348t Revised cardiac risk index (RCRI), 274-277, 275t, 276f, 278f RFLPs (restriction fragment length polymorphisms), 9 Rh immunoglobulin (RhoGAM), for immune thrombocytopenic purpura, 569 Rhabdomyolysis, 367, 368b hyperphosphatemia in, 791 Rhabdomyoma, cardiac, 156 Rheumatic diseases, approach to, 818-822. See also Arthritis; Soft tissue disorders, nonarticular. biopsy in, 821 history and examination in, 818-820, 819t, 820f laboratory testing in, 820-821, 821t radiographic studies in, 821 summary of, 822 Rheumatic fever, 92 arthritis in, 986 diagnostic criteria for, 92, 92t mitral regurgitation secondary to, 89-90 mitral stenosis secondary to, 87-89, 88f tricuspid stenosis secondary to, 91 Rheumatic manifestations of HIV infection, 1026 spondyloarthropathies, 829-830 Rheumatic manifestations of systemic disorders, 878-882, 879t endocrine, 881-882, 881t future prospects for, 882b gastrointestinal, 879t, 880-881 hematologic, 879-880, 879t malignant, 878, 879t Rheumatoid arthritis, 819t, 823-828 amyloidosis with, 330-331 clinical features of, 824-826, 825t coal dust exposure and, 237 diagnosis of, 826 differential diagnosis of, 826 epidemiology of, 823 future prospects for, 828b genetics of, 823-824 juvenile, fever in, 922 with large granular lymphocyte leukemia, 537 neutropenia in, 537 overview of, 823 pathology of, 823 pathophysiology of, 823-824, 824t, 825f pleural effusion in, 250 pulmonary manifestations of, 233-234, 234t, 825-826 silicosis and, 237 summary of, 828 treatment of, 826-828, 827t Rheumatoid factor diagnostic significance of, 820-821, 826 infective endocarditis and, 962-963 in Sjögren syndrome, 855-856 vasculitis associated with, 825-826 Rheumatoid nodules, 825-826 Rhinitis, 945-946, 948 RhoGAM (Rh immunoglobulin), for immune thrombocytopenic purpura, 569 Ribonucleic acid. See RNA (ribonucleic acid). Ribosomal RNA (rRNA), 2-4

1273

Ribosomes, 4 Richter syndrome, 548 Rickets, 797-798, 798f-799f hypophosphatemic, 292, 792-793 phosphatonins and, 781 vitamin D–dependent, 789 vitamin D–resistant, 792-793 Rickettsiae, 885 laboratory isolation of, 902 Rickettsial diseases, 916 Rickettsialpox, 970 Riedel struma, 674 Right dominant circulation, 23-24 Right heart failure, constrictive pericarditis with, 147 Right middle lobe syndrome, 220 Right ventricular failure in chronic obstructive pulmonary disease, 216 dilated cardiomyopathy with, 151 hepatic congestion in, 70 hypoglycemia in, 724 jugular venous pressure in, 36 mitral regurgitation with, 90 mitral stenosis with, 88-89 nausea and vomiting in, 35 in pregnancy, 163 pulmonary embolism with, 172 in pulmonary hypertension, idiopathic, 244 pulmonic regurgitation with, 91 in restrictive cardiomyopathy, 154 tricuspid regurgitation secondary to, 91 ventricular septal defect with, 77 Right ventricular hypertrophy, electrocardiography in, 49f, 50, 50t Right ventricular infarction, 110-111, 115, 115f Right ventricular outflow tract obstruction, 79 pregnancy in patient with, 163 in tetralogy of Fallot, 81 Rigidity, in movement disorders, 1109 Rigors, 911 intra-abdominal abscess with, 975 Riluzole, for amyotrophic lateral sclerosis, 1172-1173 Rimonabant, 633 Rings, esophageal, 411-412 Rippling muscle disease, 1186t Risedronate for osteoporosis, 807-809, 808t for Paget disease of bone, 814-816, 815t Risk factor modification. See also Lifestyle modification. in angina pectoris, 102, 102t in peripheral arterial disease, 165-166 in renal artery stenosis, 347 Risk reduction absolute, 18 relative, 18 Rituximab, 626t for B-cell acute lymphoblastic leukemia, 518 central nervous system infections and, 942-943, 943t for chronic lymphocytic leukemia, 548-549 for cold agglutinin disease, 528 for diffuse aggressive non-Hodgkin lymphomas, 545 for factor VIII inhibitors, 577 for follicular lymphomas, 544 for hairy cell leukemia, 549 hepatitis B reactivation associated with, 1029-1030 for immune thrombocytopenic purpura, 568-569 for mantle cell lymphoma, 545 for rheumatoid arthritis, 827, 827t for systemic lupus erythematosus, 838 for Waldenström macroglobulinemia, 553 River blindness, 1040, 1040t RNA (ribonucleic acid). See also Messenger RNA (mRNA); Ribosomal RNA (rRNA); Transfer RNA (tRNA). cap of, 3, 5 catalytic, 3-4 gene regulation and, 4-5 microRNAs, 5 synthesis of, 2-4, 3f RNA polymerases, 2-3, 3f gene expression and, 5 inhibition of, by toxins and antibiotics, 4 Rocky Mountain spotted fever, 916 Romano-Ward syndrome, 142-143 Romiplostim, 499 Rosiglitazone, 710t-713t, 712-713

1274

Index

Rotavirus infection, 981-982, 981t Roth spots, 962t r-PA (reteplase), 112, 112t RPGN. See Rapidly progressive glomerulonephritis (RPGN). rRNA. See Ribosomal RNA (rRNA). RSV (respiratory syncytial virus) infection, 219 Rub pericardial, auscultation of, 44, 145 pleural, 195 Rubella, arthritis secondary to, 986 Rubral tremor, 1114, 1126 RV (residual volume), 207-208, 207f S S wave, 47, 47f, 49 Sacroiliitis in inflammatory bowel disease, 434 in spondyloarthropathies, 829-833, 830t, 832f Saddle embolus, 262 Safer sexual practices, 1026 Sagittal sinus thrombosis, septic, 1162 Salicylates acidosis caused by, 318 liver damage caused by, 472 overdose of, 264t prostaglandin inhibition by, 724 tinnitus caused by, 1100-1102 Salivary gland biopsy, in Sjögren syndrome, 856 Salivary gland dysfunction, in Sjögren syndrome, 855, 856t Salmeterol, in chronic obstructive pulmonary disease, 217-219 Salmonella, 886 Salmonella Paratyphi, 912t, 913 Salmonella Typhi, 912t, 913 Salmonellosis acute, 980, 981t, 984 in HIV-infected patients, 1024, 1025t Salt, dietary. See also Sodium restriction. for diabetic patient, 705 hypertension and, 179 Sarcoidosis, 231-233 clinical manifestations of, 231-232, 232t corticosteroids for, 233, 233t fever in, 922 hypercalcemia in, 232-233, 786 immune dysfunction in, 231-232 lymphadenopathy in, 919 musculoskeletal manifestations of, 882 pulmonary manifestations of, 190-191, 226-227, 227f, 228t-229t, 231-233 radiographic staging of, 232, 232t renal manifestations of, 335 restrictive cardiomyopathy in, 153-154 Sarcolemma cardiac, 25 action potential and, 118 skeletal muscle, 1182 Sarcomeres, 25, 25f Sarcoplasmic reticulum, 25, 26f Sargramostim, 627 SARS (severe acute respiratory syndrome), 258b, 913, 955, 1037 Sausage digits. See Dactylitis. Saw palmetto, for benign prostatic hyperplasia, 755 Scarlet fever, 915 Schatzki rings, 412 Schilling test, 391-392, 525 Schistocytes, 528 Schistosomiasis, 1039-1040, 1040t Schizoaffective disorder, 1081 Schizophrenia, 1081 Schizophreniform disorder, 1081 Schmidt syndrome, 675, 681 Schwannoma, vestibular, 1101-1102, 1102f Scintigraphy. See Radionuclide imaging. Scleredema (of Buschke), 847t Scleroderma. See Systemic sclerosis (scleroderma). Scleromyxedema, 847t Scoliosis, 251-252, 1119 Scotomas, 1096, 1099

Screening tests, 17, 17t, 19, 20b for women, 733, 734t Scrofula, 919 Scrotum, benign diseases of, 768-769 Scurvy, 565-566 Seborrheic dermatitis, in HIV-infected patients, 1020t Secondary research studies, 17, 17t Secretin test for chronic pancreatitis, 451 in Zollinger-Ellison syndrome, 426-427 Secretory diarrhea, 397-398, 397t-398t Sedative-hypnotics, abuse of, 1224-1229, 1225t-1228t Seizure(s), 1141. See also Epilepsy. brain abscess causing, 1159-1160 brain tumor causing, 1154-1156 classification of, 1142-1143 in cysticercosis, 1040-1041 electrical, 1143 febrile, 1147, 1150 generalized, 1142 primary, 1145-1146, 1145f secondary, 1144 incidence of, 1141 nonconvulsive, 1061 non-epileptic disorders resembling, 1148-1149, 1148t partial, 1142-1144, 1143t postictal coma associated with, 1058, 1061 psychogenic non-electrical, 1148 in stroke, acute, 1128, 1132 subclinical, 1143 symptomatic, causes of, 1141, 1142t terminology for describing, 1142-1143 in traumatic brain injury, early-onset, 1137-1138 Seizure disorder, 1141 Seizures, febrile, 1147, 1150 Selective estrogen receptor modulators (SERMs). See Raloxifene. Selegiline, 1112, 1112t Seminoma, 766-767 Semiology, of seizure, 1142-1143 Sense strand, 3 Sensitivity of a test, 17-18, 17t, 600 Sepsis, 925-932 acute respiratory distress syndrome in, 262 definitions related to, 925, 926t diagnosis of, 929-930 epidemiology of, 925-926 hypocalcemia in, 790 hypoglycemia in, 724 management of, 930-932, 930t-931t natural history of, 926f neutropenia with, 537 pathogenesis of, 926-928, 927f pathogens associated with, 925-926, 927t postanginal, 949 Sepsis syndrome, 925-932 clinical manifestations of, 928-929, 929t definition of, 925, 926t diagnosis of, 929-930 future prospects for, 931b-932b management of, 930-932, 930t-931t natural history of, 926f pathogenesis of, 926-928 systemic inflammatory response syndrome and, 263, 925, 926t Septic arthritis, 818, 819t, 820, 985-986, 986t in gonorrhea, 1003 vs. gout, 866 in sickle cell disease, 879 Septic bursitis, 874-875, 987 Septic shock, 262, 263t clinical manifestations of, 929 definition of, 925, 926t epidemiology of, 925-926 management of, 930-932 natural history of, 926f pathogenesis of, 926-928 Septicemia, 925, 926t. See also Bacteremia. Sequestra, of bone, 988 SERMs (selective estrogen receptor modulators). See Raloxifene. Serotonin agonists, for migraine, 1088 Serotonin syndrome, 1084 Serum ascites-albumin gradient, 481, 482t

Serum glutamic-oxaloacetic transaminase (SGOT), 457-458, 457t jaundice and, 464 Serum glutamic-pyruvic transaminase (SGPT), 457-458, 457t jaundice and, 464 Sex differences in biology and physiology, 731-733 in heart failure, 745-746 in socialization and economics, 733 Sexual assault, 748 Sexual dysfunction. See also Erectile dysfunction. in chronic kidney disease, 374 Sexual history of adolescent, 735 of reproductive-age woman, 737 Sexuality, in menopausal women, 744, 744t Sexually transmitted infections (STIs), 998-1007 in adolescents, 735 classification of, 998 epidemiology of, 998 errors in approach to, 998 with genital ulcers, 998-1002, 999t. See also Herpes simplex virus infection; Syphilis. human papillomavirus–associated, 1006 with urethritis, cervicitis, and PID, 1003-1005. See also Gonorrhea. vaginitis as, 1005, 1005t SGOT. See Serum glutamic-oxaloacetic transaminase (SGOT). SGPT. See Serum glutamic-pyruvic transaminase (SGPT). Shawl sign, 851 Shift work sleep disorders, 1066 Shiga toxin, 980 hemolytic uremic syndrome and, 353t, 354, 355f, 587 Shigella, 886 Shigellosis, acute, 980-982, 981t, 984 Shingles. See Herpes zoster. Shock, 262-263. See also Cardiogenic shock; Neurogenic shock; Septic shock. Short QT syndrome, 143 Short tandem repeats (STRs), 7-9 Shotgun sequencing, 9 Shoulder, periarthritis of, in hyperthyroidism, 882 Shoulder pad sign, 879-880 Shoulder-hand syndrome, 881 Shunt, hypoxemia caused by, 206, 206f-207f Shunt lesions, cardiac, 76f, 76t, 206. See also specific lesions. assessment of, 60 noncardiac surgery in patient with, 282 Shunt nephritis, 326 Shy-Drager syndrome, 1113-1114 SIADH. See Syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Sibutramine, 633, 705 Sicca complex, rheumatoid arthritis with, 825-826 Sick sinus syndrome, 123f, 126 Sickle cell β-thalassemia, 531, 879 Sickle cell disease, 522f, 530-531, 530t infections in, 1030 renal manifestations of, 320, 332, 530 rheumatic manifestations of, 879 Sideroblastic anemias, 522-523 Sigmoidoscopy, 402 for bleeding, 388 for colorectal cancer screening, 442-443, 443t Signal transduction, calcium in, 772 Signal transduction inhibitors, 625-626, 626f, 626t. See also Tyrosine kinase inhibitors. Sildenafil for erectile dysfunction, 762 for pulmonary hypertension, in systemic sclerosis, 848-849 for Raynaud phenomenon, 847, 848t Silencer sites, 3f, 5 Silencing of genes, 5-6 Silent mutations, 7, 10 Silicosis, 228t-229t, 237 Single nucleotide polymorphisms (SNPs), 7-8, 8f Single ventricle heart, 82 Single-photon absorptiometry, of bone mass, 804-805, 807t

Index Single-photon emission computed tomography (SPECT) intracranial imaging with, 1056-1057 before epilepsy surgery, 1148 myocardial perfusion imaging with, 57-58 Sinoatrial exit block, 122, 123f Sinoatrial (sinus) node, 24, 24f action potential in, 118, 119f autonomic influence on, 24-25, 118 Sinoatrial (sinus) node dysfunction, 122, 123f Sinus arrest, 122, 123f Sinus bradycardia, 122, 123f after myocardial infarction, 114 Sinus node. See Sinoatrial (sinus) node. Sinus pause, 122, 123f Sinus tachycardia, after myocardial infarction, 113-114 Sinus venosus defect, 75, 77 Sinuses, cancers of, 606 Sinuses of Valsalva, 23-24 aneurysm of, infective endocarditis causing, 961-962, 966 Sinusitis, 946 fever in, 922 headache in, 1091 subdural empyema secondary to, 1160-1161 venous sinus thrombosis secondary to, 1162 Sinusoidal obstruction syndrome, 486 Sipple syndrome, 689 Sirolimus (rapamycin) for lymphangioleiomyomatosis, 239 mechanism of action, 378, 378f side effects of, 378 Sirolimus-eluting stents, 104-105 Sitagliptin phosphate, 710t-713t 6-minute walk test, 195-197, 209, 217 Sjögren syndrome, 855-857 clinical features of, 855, 856t diagnosis of, 855-857 differential diagnosis of, 856-857 future prospects for, 857b pulmonary manifestations of, 233-234, 234t, 856t renal tubular acidosis in, 320 secondary, 855 in primary biliary cirrhosis, 881 in rheumatoid arthritis, 825-826 in systemic lupus erythematosus, 835 treatment of, 857, 857t Skeleton. See also Bone. calcium homeostasis and, 773-775, 773f magnesium homeostasis and, 782 phosphate homeostasis and, 778-780, 779f Skilled nursing facilities, 1207 Skin and soft tissue infections, 969-974 deeper, 969, 973-974 in HIV-infected patients, 1020, 1020t necrotizing, 973-974 superficial, 969 circumscribed, 969-973, 970t diffuse, 972-973, 972t Skin cancer, 614 in kidney transplant recipients, 378 Skin examination, in kidney disease, 298, 375 Skin lesions. See also Rash. in disseminated mycoses, 1031-1032, 1032f of returning traveler, 1038 in systemic lupus erythematosus, 835, 837t Skin tests, for microbial antigens, 899 Skipped beats, 33-34, 122, 131 Sleep, neurobiology of, 1064, 1065f Sleep apnea, 190-191, 247b, 1064-1066 central, 245-246 hypertension secondary to, 177t, 178 obstructive, 245-246, 1065-1066 prevalence of, 190 Sleep disorders, 1064-1067. See also Sleep-related breathing disorders; Sleep-related movement disorders. of circadian rhythm, 1066 fibromyalgia syndrome and, 876 hypersomnia syndromes, 1066 hypnotic agents for, 1064, 1066, 1066t insomnia, 1064 circadian rhythm and, 1066 familial fatal, 884-885, 1163 International Classification of, 1064

Sleep disorders (Continued) parasomnias, 1066-1067 perimenopause and, 742 wakefulness-promoting agents for, 1066, 1066t Sleep hygiene, 1064, 1065t Sleep terrors, 1066-1067 Sleep-related breathing disorders, 245. See also Sleep apnea. in chest wall disease, 252 prevalence of, 190, 245 Sleep-related movement disorders, 1067, 1067t Sleepwalking, 1066-1067 Slit diaphragm, 288-289, 289f, 323 Small airways disease, 213-214, 216-219. See also Chronic obstructive pulmonary disease (COPD). Small bowel follow-through, 405, 405f in Crohn disease, 433, 434f Small intestine absorption in, 389-390 bacterial overgrowth in, 393-395, 398 in chronic pancreatitis, 452 barium studies of, 391, 394 biopsy of, 391, 393t, 394 bleeding from, 388 computed tomography of, 406 endoscopy of, 402 fluid in, 396 motility of, 416 Small lymphocytic lymphoma. See Leukemia, chronic lymphocytic. Small-duct sclerosing cholangitis, 434 Smallpox, 970, 1046-1047, 1047f Smoke inhalation, 264-265, 264t Smoking bladder cancer and, 611 Buerger disease and, 169 cancer risk and, 598-599, 599t chronic obstructive pulmonary disease and, 189-190, 213-214, 215f, 217 as chronic bronchitis, 216 as emphysema, 215 as small airways disease, 216 coronary artery disease and, 97 decline in lung function and, 214, 215f erectile dysfunction and, 759, 759t esophageal cancer and, 606 head and neck cancer and, 606 inflammatory bowel disease and, 431 interstitial lung disease and, 225, 227 desquamative pneumonia, 231 respiratory bronchiolitis–associated, 231 Langerhans cell histiocytosis and, 238-239 lung cancer and, 266-268, 603 lung disease and, 194 osteoporosis and, 802 pancreatic cancer and, 609 penile cancer and, 765 renal cell carcinoma and, 612 staining of fingers in, 194-195 venous thromboembolism and, 584 by women, 730-731 diabetes and, 746 menopause and, 743, 745 Smoking cessation, 116-117 in chronic obstructive pulmonary disease, 217 by women, 730 SNPs (single nucleotide polymorphisms), 7-8, 8f Sodium. See also Hypernatremia; Hyponatremia. diuretics and, 307-308, 308t fluid compartments and, 305, 306f renal transport and, 292-294, 296 mutations affecting, 296, 320-321 serum osmolality and, 308 urinary, in acute kidney injury, 362t volume depletion and, 306-307 Sodium channel blockers, mechanism of action, 307-308, 308t Sodium channelopathies, 1186t, 1187-1188 Sodium nitroprusside. See Nitroprusside. Sodium oxybate, in narcolepsy, 1066 Sodium restriction. See also Salt, dietary. in cirrhotic ascites, 482 in heart failure, 72 for volume excess, 307-308

1275

Sodium-potassium pump (Na+,K+-ATPase) intestinal, 396, 396f-397f renal, 291-292, 294 Fanconi syndrome and, 319 Soft tissue disorders, nonarticular, 873-877 bursitis, 873-875, 874t septic, 874-875, 987 classification of, 873 diagnosis of, 874, 874t fibromyalgia syndrome, 873, 875-877, 876t pathogenesis of, 873 tendinitis, 873-875, 875t Soft tissue infections. See Skin and soft tissue infections. Somatization disorder, 1081-1082 Somatoform disorders, 1078t-1079t, 1081-1082 Somatostatin gastric, 415-416, 415f, 419-420 growth hormone and, 661, 661t insulin secretion and, 700 thyroid-stimulating hormone and, 661t, 664 for variceal hemorrhage, 481 Somatostatin analogues. See also Octreotide. for carcinoid syndrome, 443-444 Somatostatin-receptor scintigraphy, 427 Somogyi effect, 708 Sorafenib, 594, 625, 626t for hepatocellular carcinoma, 484-485 for renal cell carcinoma, 612 Sore throat, 947-950, 948t. See also Pharyngitis. Sotalol, 137t-138t, 139 Spasticity, 1108-1109 Specificity of a test, 17-18, 17t, 600 SPECT. See Single-photon emission computed tomography (SPECT). Spermatogenesis, 691 defective, 691, 693-694 Spherocytosis, hereditary, 528, 528t Sphincter of Oddi, 488, 489f dysfunction of, 494 endoscopic procedures of, 402-403, 493-494 Spinal cord in encephalomyelitis, acute disseminated, 1170 neuromyelitis optica of, 1099, 1169 tethered, 1119 transverse myelitis of acute, 1169-1170 optic nerve disease with, 1099 Spinal cord compression cancer-associated, 617 cervical spondylosis with, 1093-1094 in rheumatoid arthritis, 824 in spondyloarthropathies, 831 Spinal cord injury, traumatic epidemiology of, 1136 management of, 1138-1140 prognosis of, 1140, 1140t Spinal cord stimulation, for refractory angina, 105 Spinal cord syndromes, 1138-1139 Spinal cord tumors, 1157-1158 extended from brain, 1155 meningioma, 1157 rapid recurrence of, 1154 Spinal epidural abscess, 987, 1161-1162, 1161f Spinal malformations, 1119 Spinal muscular atrophy, 1173 Spinal shock, 1139 Spinal stenosis, 1095 lumbar, 165 Spirillum minus, 885 Spirochetes, 885 Spirometry, 195-197, 207-208, 207f Spironolactone. See also Aldosterone antagonists. for cirrhotic ascites, 482 in heart failure, 72 mechanism of action, 307-308, 308t potassium secretion and, 296 for resistant hypertension, 184 Spleen, lymphocytes in, 540 Splenectomy for immune thrombocytopenic purpura, 569 infections subsequent to, 1030 for thrombocytopenia, 567 Splenic abscess, 976-977, 976t Spliceosome, 3

1276

Index

Splicing, of messenger RNA, 3-4 Splinter hemorrhages, infective endocarditis with, 962t Spondyloarthropathy(ies), 819t, 829-833, 830t, 832f, 833b undifferentiated, 829-830 Spontaneous bacterial peritonitis, 479, 482-483, 977, 978t Sprue, nontropical. See Celiac disease. Spur cell anemia, 529 Sputum color of, 193 production of, 193 Sputum sample culture of, 903, 954 in pneumonia, 254-255, 954-955, 955t nosocomial, 994 Pneumocystis jiroveci, 257 tuberculous, 958 Squamous cell carcinoma of esophagus, 439, 606 of head and neck, 606 of lung, 266-267, 269, 603 of penis, 765-766 of skin, 614 Square-root sign, in constrictive pericarditis, 147-148, 148f ST segment, 47, 47f. See also ST-segment abnormalities. Stability genes, 595t, 596 Staining of microorganisms, 898, 899f Standard precautions for blood and body fluids, 992, 1026 Staphylococcal folliculitis, in HIV-infected patients, 1020t Staphylococci, 886-887 coagulase-negative, 887 Staphylococcus aureus infection, 886-887 cutaneous, 969-970 infective endocarditis in, 913, 961-963 antibiotics for, 966 surgery for, 966 lymphadenitis in, acute suppurative, 919 methicillin-resistant (MRSA), 886-887, 956 in bone, 987 in neutropenic febrile patients, 1033 in skin and soft tissues, 969-970, 972 in urinary tract, 990 osteomyelitis in, 987 chronic, 988 pneumonia in, 255-256, 255t, 956, 959t nosocomial, 994 sepsis in, 912t, 913 septic arthritis in, 985-986 septic bursitis in, 987 toxic shock syndrome in, 916 Staphylococcus epidermidis, 887 Staphylococcus saprophyticus, 887 Starvation, refeeding in, 793 Stasis ulcers, 971 Statins, 647, 647t after acute coronary syndrome, 116-117 in angina, stable, 102 in antihypertensive regimen, 180 in chronic kidney disease, 374-376 C-reactive protein and, 97 in diabetic dyslipidemia, 704 perioperative, with noncardiac surgery, 279 in peripheral arterial disease, 166 for stroke prevention, 1132 Status asthmaticus, 224 Status epilepticus, 1151, 1152t nonconvulsive, 1058 Steatorrhea. See also Fecal fat analysis. in chronic pancreatitis, 451-452 Steatosis, 474 Stem cell therapy, 13-14 myocardial, 74b Stem cell transplantation, 499-500, 625. See also Bone marrow transplantation. for acute lymphoblastic leukemia, 518 for acute myeloid leukemia, 516-517 for chronic lymphocytic leukemia, 548-549 for chronic myelogenous leukemia, 500, 513 colony-stimulating factors for, 627 for follicular lymphomas, 544 for myelodysplastic syndrome, 504-505

Stem cell transplantation (Continued) nonmyeloablative, 500 for paroxysmal nocturnal hemoglobinuria, 502-503 peripheral blood, 500, 625 for diffuse aggressive non-Hodgkin lymphomas, 545 for multiple myeloma, 552 for primary myelofibrosis, 511 for systemic lupus erythematosus, 585 for systemic sclerosis, 848 umbilical cord blood, 500, 625 Stem cells cancer, 596-597, 615b, 1158b hematopoietic, 496-498, 498f clonal disorders of, 507, 508t maturation defects of. See Hematopoietic failure. plasticity of, 498 in lung, 266-267 STEMI. See Myocardial infarction, ST-segment elevation (STEMI). Stenting for carotid stenosis, 1130 for iliac stenosis, 166f intracoronary, 96f, 104-105 anticoagulation following, 116-117 noncardiac surgery and, 277 for vasospastic angina, 106 for renal artery stenosis, 347-348 for superior vena cava syndrome, 618 Steroid hormones, biosynthesis of, 679, 680f Steroid therapy. See Corticosteroid therapy. Stevens-Johnson syndrome, oral lesions in, 947 Stiff-hand syndrome, diabetic, 881 Stiff-person syndrome, 1188 Stimulants. See Wakefulness-promoting agents. STIs. See Sexually transmitted infections (STIs). Stomach, 414-429. See also Gastric entries. anatomy of, 414-415, 415f diseases of. See also Gastritis; Peptic ulcer disease. delayed gastric emptying, 427-428, 427t rapid gastric emptying, 428 volvulus, 428-429 endoscopy of, 401, 403f motor physiology of, 416 secretions of, 414-416, 415f Stomatitis, 946 aphthous, 947 candidal, 946 in HIV-infected patients, 1020 hematopoietic failure presenting as, 950 Vincent, 947 Stomatocytosis, hereditary, 528t Stool sample. See also Fecal fat analysis. blood testing, 442-443, 443t DNA testing, 442-443, 443t in infectious diarrhea, 982 in HIV-infected patient, 1024-1025 Storage pool disease, 572t, 573 Streptococcal infections, 887 glomerulonephritis secondary to, 324-325, 325t group A, 887 acute suppurative lymphadenitis in, 919 erysipelas in, 972 pharyngitis in, 948, 1115 rheumatic fever and, 92 toxic shock syndrome and, 916 Streptococcus pneumoniae infection, 887 acute meningitis in, 934, 936-937 immune response to, 896 immunization against. See Pneumococcal vaccine. pneumonia in, 254-256, 255t, 887, 955-956, 959, 959t in sickle cell disease, 1030 Streptococcus viridans infection, 887 endocarditis in, 961-962 Streptokinase, 112, 112t Stress gastritis secondary to, in critical illness, 417-419, 418t hyperglycemia in, 706-707 hypoglycemia in, 724 Stress disorder, acute, 1080-1081 Stress proteins, 5

Stress testing in angina pectoris, 99-102, 101f echocardiographic, 55-56 electrocardiographic, 53-55 myocardial perfusion imaging with, 57-58 before noncardiac surgery, 276 pharmacologic, 55, 57-58 in angina pectoris, 99-102 before noncardiac surgery, 276 Stress-induced cardiomyopathy, 150t Striatonigral degeneration, 1113-1114 Stroke blood pressure lowering after, 183-185, 1132 definition of, 1123 dementia secondary to, 1074 diagnosis of, 1128, 1129f differential diagnosis of, 1128 epidemiology of, 1123, 1124t in evolution, 1125-1126 future prospects for, 1135b hemorrhagic, 1128, 1132-1133, 1132t-1133t. See also Subarachnoid hemorrhage. infective endocarditis complicated by, 962-963 ischemic, 1123, 1125-1126. See also Transient ischemic attack. brainstem, 1126 causes of, 1125, 1125t-1126t, 1126f cerebral edema and, 1125, 1131 imaging in, 1128, 1129f lacunar, 1126 major syndromes in, 1126-1128, 1127t management of, 1130-1132, 1131f pathogenesis of, 1125 risk factors for, 1124t secondary prevention of, 1132 vs. transient ischemic attack, 1125-1126 in young patients, 1125, 1126t, 1128 neuroprotective agents in, 1125, 1131, 1135b prevention of primary, 1128-1130 secondary, 1132 risk factors for, 1124t atrial fibrillation, 126 estrogen therapy and, 743-744 gender or ethnicity and, 746 hypertension, 174, 175f perioperative beta blockers and, 279 Stroke volume, 27-28 heart failure and, 68-69, 69f Strongyloidosis, 1039, 1040t Strontium, for osteoporosis, 809 STRs (short tandem repeats), 7-9 Struma ovarii, 674-675 Struvite stones, urinary, 343, 343t ST-segment abnormalities, 51-53, 54f in angina pectoris, 99-101, 99t, 100f-101f in Brugada syndrome, 143-144 in myocardial infarction, 51-53, 52f-53f in myocardial ischemia, 51-53 during exercise, 55 in pericarditis, acute, 145, 149 Stunning, myocardial, 98 Sturge-Weber syndrome, 1121 Subacute bacterial endocarditis, glomerulonephritis secondary to, 326 Subaortic stenosis, 78-79 Subarachnoid hemorrhage causes of, 1132, 1132t. See also Aneurysm(s), intracranial. clinical manifestations of, 1134 coma associated with, 1058-1059 complications of, 1134, 1134t diagnosis of, 1134 headache of, 1086, 1090-1092 Subdural empyema, 1160-1161 Subendocardial infarction. See Myocardial infarction, non–ST-segment elevation (NSTEMI). Subphrenic abscess, 976t, 977 Substitution mutations, 7, 7t Succinylcholine, apnea associated with, 1193 Sucralfate, 418, 424 Sudden cardiac death, 135, 135t arrhythmogenic right ventricular cardiomyopathy/ dysplasia and, 154-155 in Brugada syndrome, 143-144

Index Sudden cardiac death (Continued) in hypertrophic cardiomyopathy, 152-153 implantable cardioverter-defibrillators and, 142-143 in short QT syndrome, 143 Sulfasalazine for inflammatory bowel disease, 436 for rheumatoid arthritis, 827 for spondyloarthropathies, 832 Sulfonylureas, 708-709, 710t-713t hypoglycemia caused by, 723-724, 726t Sulfosalicylic acid test, 300 Sulindac, liver damage caused by, 472 Sumatriptan for cluster headache, 1090 for migraine, 1088 Sunitinib, 594, 625, 626t for renal cell carcinoma, 612 Superior vena cava syndrome cancer-associated, 617-618 in lung cancer, 267 chronic mediastinitis with, 251 Supplementary motor seizures, 1144 Suppressor elements, 5 Suppurative phlebitis, 968 Supraventricular tachyarrhythmias, after myocardial infarction, 113-114 Supraventricular tachycardias, 124 cardiomyopathy secondary to, 151 diagnostic features of, 132, 132t Surfactant, 198, 201 acute respiratory distress syndrome and, 262 infant respiratory distress syndrome and, 189 Surgery in anticoagulated patient, 590 for cancer, 622 long-term effects of, 619t, 620 venous thromboembolism secondary to, 584-585 prophylaxis of, 587-588 Surgery, cardiac, 158-161. See also Cardiac transplantation; Coronary artery bypass grafting (CABG). Surgery, noncardiac cardiovascular disease and, 160-161, 161t, 281-282 arrhythmias, 162, 281 congenital heart disease, 282 heart failure, 162, 281 hypertrophic cardiomyopathy, 281-282 valvular, 162, 281 incidence of cardiac complications in, 274 intraoperative risk reduction strategies, 279-280 myocardial infarction following, 161-162, 274 analgesia and, 279-280 management of, 280-281 monitoring for, 280 postoperative care for, 280-281, 282b preoperative care for, 274-283, 282b cardiac risk assessment, 274-279, 275t, 276f cardiac risk modification, 277-279, 278f identification of patients at risk, 274, 275t invasive cardiac testing in, 277 noninvasive cardiac testing in, 276 risk level of procedure and, 274-276, 275t Surgical site infections, 997 Swallowing, 408. See also Dysphagia; Odynophagia. Swan-Ganz catheter. See Pulmonary artery catheter. Swan-neck deformity, in rheumatoid arthritis, 824 Sweat test, 221 Sweet syndrome, 435, 878 Sydenham chorea, 1115 Sympathetic nervous system cardiac impulses and, 118 heart failure and, 68f, 69-70, 73 metabolic syndrome and, 700-701 Sympatholytic agents, central, 179t-182t Syncope, 34-35, 131, 133-134, 133t, 134f aortic stenosis with, 84 in Brugada syndrome, 143-144 convulsive, 1148-1149 in hypertrophic cardiomyopathy, 152-153 in short QT syndrome, 143 Syndrome of apparent mineralocorticoid excess, 178 Syndrome of inappropriate secretion of antidiuretic hormone (SIADH), 309-311, 310t, 619t Syndrome X, 98

Synovial fluid analysis, 820, 821t in calcium pyrophosphate deposition disease, 867f, 869 in gonorrhea, 1003 in gout, 866-867, 867f in infective arthritis, 985 in Lyme disease, 917 in osteoarthritis, 871 in rheumatoid arthritis, 826 Synovitis, 818-819, 820f in rheumatoid arthritis, 824, 826 Syphilis, 999t, 1000-1002 central nervous system complications of, 938-939, 1001-1002 epidemiology of, 1000-1001 in HIV-infected patients, 1021 inguinal lymphadenopathy in, 920 laboratory diagnosis of, 1001-1002, 1002t latent, 1001 natural history of, 1001 oral lesions in, 947 pathogenesis of, 1001 treatment of, 1001-1002, 1002t Syringomyelia, 1119-1120 Systemic inflammatory response syndrome, 263, 925. See also Sepsis. acute pancreatitis with, 445 cytokines in, 928t definition of, 926t management of, 930-932 Systemic lupus erythematosus, 819t, 834-840 antiphospholipid antibodies in, 356, 585, 835, 837-838, 837t, 842-843 bone health and, 839-840 cardiovascular disease and, 839 clinical manifestations of, 835, 836t diagnosis of, 835-836, 837t epidemiology of, 834 fever in, 922 hormonal therapy and, 839 immune thrombocytopenic purpura in, 568-569 malignancy and, 839 mixed connective tissue disease and, 836-837 nephritis in, 324-326, 326t, 835, 837t, 838 neutropenia in, 537 overview of, 834 pathogenesis of, 834 pleural effusion in, 250 pregnancy and, 838-839 pulmonary manifestations of, 233-234, 234t vs. rheumatoid arthritis, 826 treatment of, 837-838 valvular disease in, 963 Systemic sclerosis (scleroderma), 844-849 clinical features of, 845-846, 846t differential diagnosis of, 846-847, 847t epidemiology of, 844 esophageal dysmotility in, 412, 412t, 846, 846t future prospects for, 849b overview of, 844 pathology of, 844, 845f patient care and treatment in, 847-849, 848t pulmonary manifestations of, 233-234 renal crisis in, 352 Systemic vascular resistance calculation of, 29 exercise and, 31 in shock, 263t Systole, 22-23, 26-30, 27f T T lymphocytes. See also CD4 T cells. fundamental biology of, 539-540, 892-893, 895-896 antigenic diversity and, 893-894 antiviral defense and, 897 in lymph nodes, 540 peripheral blood, 540-541 in rheumatoid arthritis, 823-824, 824t, 825f T tubules, 25, 26f T wave, 47, 47f Tabes dorsalis, 939, 1001

1277

Tachyarrhythmias, 124-131 atrial. See Atrial tachyarrhythmias. atrioventricular nodal (junctional), 127-129, 128f classification of, 124 nonpharmacologic therapy of, 141-143 ventricular. See Ventricular tachyarrhythmias. Tachycardia in asthma, severe, 194 atrial, 124-125, 125f reduced coronary flow in, 28 sinus, after myocardial infarction, 113-114 ventricular. See Ventricular tachycardia. Tachycardia-bradycardia syndrome, 122, 123f Tacrolimus, 377-378, 378f Tadalafil, 762 Taenia solium infection, 1040-1041, 1040t TAFI (thrombin activator fibrinolysis inhibitor), 562-563, 580-581, 590b Takayasu arteritis, 169, 350, 859f, 861 Takotsubo cardiomyopathy, 150t Tamm-Horsfall protein, 300-301 Tamoxifen for breast cancer, 626-627 for gynecomastia, 695-696 Tamponade, cardiac, 146-147 jugular venous pulse and, 36, 37f malignant tumors with, 156 pulsus paradoxus in, 36-38, 38f vs. right ventricular infarction, 115 trauma with, 158 Tamsulosin, for benign prostatic hyperplasia, 754-755 Tandem repeats, 6-9 Tangier disease, 1176t Tanner stage, of breast development, 735, 736f Tapeworm, 1040-1041, 1040t Targeted cancer therapy, 625-626, 626f, 626t TATA box, 5 TBG (thyroxine-binding globulin), 670-671, 676 Technetium-99m, in gastrointestinal imaging, 388, 406-407 TEE. See Transesophageal echocardiography (TEE). Tegaserod, for irritable bowel syndrome, 384-385 Telangiectasia, hereditary hemorrhagic, 566 Telmisartan, for hypertension, 179t-180t, 180 Telomerase, aging and, 1198 Telomeres, aplastic anemia and, 501 Temozolomide, for malignant glioma, 1156 Temperature regulation, 910 Temporal arteritis, 169, 859f, 861-862, 1092 Temporal lobe epilepsy, 1145 PET imaging in, 1148 Temporal lobe lesions, 1069f, 1070-1071, 1070t Temporal lobe seizures, 1143, 1143t Temporal lobe tumors, 1155 Temsirolimus, for renal cell carcinoma, 612 Tendinitis, 873-875, 875t Tenecteplase (TNK-tPA), 112, 112t Tennis elbow, 873, 875 Tenosynovitis, in rheumatoid arthritis, 824 Tensilon test, 1191-1192 Tension pneumothorax, 250 Tension-type headache, 1090, 1090t Terazosin, for benign prostatic hyperplasia, 754-755 Teriparatide, 808t, 809 Terlipressin, for hepatorenal syndrome type 1, 367 Terrorism. See Bioterrorism; Chemical weapons; Radiation exposure. Testes endocrinology of, 691, 692f primary failure of, 692-694, 692t Testicular cancer, 611t, 766-767, 766t Testicular feminization, 693 Testicular torsion, 769 Testosterone, 691, 692f defects in action of, 693 deficiency of. See Hypogonadism. gonadotropins and, 666 therapy with, 693-694 for erectile dysfunction, 760 for gonadotropin deficiency, 666-667 transcriptional action of, 693 type 2 diabetes and, 703 Tests diagnostic, 17-19, 17t screening, 17, 17t, 19

1278

Index

Tetanus immunization, for travelers, 1035 Tetany, 772, 788 Tetrabenazine, for Huntington disease, 1115 Tetralogy of Fallot, 78t, 81 noncardiac surgery in patient with, 282 pregnancy in patient with, 163 Thalamus, hemorrhage in, 1132, 1133t Thalassemias, 531-532, 531t Thalidomide for multiple myeloma, 552 for oral ulcers, in HIV-infected patients, 1021 Thallium myocardial scintigraphy. See Dipyridamole stress testing. Theophylline for asthma, 223-224 in chronic obstructive pulmonary disease, 218 Thermal regulation, 1083-1085. See also Hyperthermia; Hypothermia. Thermodilution measurement, of cardiac output, 59-60, 62t Thiamine deficiency of Korsakoff syndrome caused by, 1071, 1076 neuropathy caused by, 1177 supplemental, with parenteral nutrition, 641-642 Thiazide-type diuretics in heart failure, 72 for hypercalciuria, 342t, 343 for hypertension, 179-180, 179t-180t, 183 after stroke, 1132 mechanism of action, 293-294, 307-308, 308t Thiazolidinediones, 710t-713t, 712-713 Thin basement membrane disease, 330 Third cranial nerve palsy, 1097 Thomsen disease, 1186t, 1187 Thoracentesis, of pleural effusion, 249 Thoracic outlet obstruction, 171 Thrills, 39, 42-43 Throat, examination of, 947-948 Thrombectomy, coronary, 105 Thrombin, 560-562 Thrombin activator fibrinolysis inhibitor (TAFI), 562-563, 580-581, 590b Thrombin time, 564, 565t, 575-576, 576t Thrombocythemia, essential, 509-510, 509t, 585-586 Thrombocytopenia, 566-572. See also Thrombotic thrombocytopenic purpura. bleeding time and, 556-557 with decreased platelet production, 566-567, 567f definition of, 566 with destruction of platelets, 567-568, 567f alloimmune, 569-570, 570t in disseminated intravascular coagulation, 570-571, 571t immune drug-induced, 569, 570t immune thrombocytopenic purpura, 568-570 diagnostic approach to, 566 differential diagnosis of, 566, 567f dilutional, 571-572 future prospects for, 579b heparin-induced, 569, 586, 588 investigational agents for, 499 neonatal, 569-570 pregnancy-induced hypertension with, 571 with sequestration of platelets, 567, 567f in systemic lupus erythematosus, 835, 837t, 838 Thrombocytosis, in myeloproliferative disorders, 585-586 Thromboembolectomy for acute limb ischemia, 166-167 for pulmonary embolism, 243 Thromboembolism. See also Anticoagulation; Venous thromboembolism. atrial fibrillation and, 126 in heart failure, 73 Thrombolytic therapy for acute limb ischemia, 166-167 in Budd-Chiari syndrome, 486 clopidogrel and, 110-111 for deep venous thrombosis, upper extremity, 171 in myocardial infarction, ST-elevation, 111-117 with cardiogenic shock, 115 contraindications to, 112, 113t dosing regimens of, 112, 112t selection criteria for, 110t

Thrombolytic therapy (Continued) in non–ST-segment elevation myocardial infarction, 109-110 for portal vein thrombosis, 486 for pulmonary embolism, 173, 243 selection criteria for, 110t for stroke, ischemic, 1130-1131, 1131f in unstable angina, 109-110 for venous thromboembolism, 587-588 Thrombomodulin, 561, 561f Thrombophilia, 580 inherited, 582-584, 582t, 587 Thrombophlebitis. See also Phlebitis. in lung cancer, 268t paraneoplastic, 619t septic catheter-related, 995 of jugular vein, 949, 949t suppurative, 968 in Trousseau syndrome, 171, 571 Thromboplastin, 561-562 Thrombopoietin (TPO), 497t, 498-499 Thrombosis, 580-591. See also Anticoagulation. arterial. See Arterial thrombosis. cancer-associated, 585, 616 future prospects for, 590b microvascular, in sepsis, 927-928 platelet disorders and, 585-587 vascular causes of, 580 venous. See Venous thromboembolism. Thrombotic microangiopathy, 331-332, 332t, 352-357, 353t, 354f-355f, 586-587 in antiphospholipid antibody syndrome, 356, 841-842 Thrombotic thrombocytopenic purpura, 331-332, 332t, 352-354, 353t, 354f, 586-587 microangiopathic hemolysis caused by, 528 in systemic lupus erythematosus, 838 Thrush, 946 in HIV-infected patients, 1020 Thymoma, 251, 1191-1192 Thyroglobulin, 670 autoantibodies to, 671-672, 674 serum measurements of, 671 Thyroid cancer, 677-678, 677t Thyroid function testing, in chronic kidney disease, 374 Thyroid gland, 670-678. See also Hyperthyroidism; Hypothyroidism. anatomy of, 670 autoantibodies to, 671-672, 674, 676 biopsy of, 672, 677 evaluation of, 671-672 future prospects for, 678b nodules of goiter with, 674, 676 multiple, 674, 677 solitary, 673-674, 677, 677t warm vs. cold, 671 physiology of, 670, 671f, 671t toxic adenoma of, 673-674 Thyroid peroxidase (TPO), antibodies against, 671-672, 674, 676 Thyroid scan, 671 Thyroid storm, 672 Thyroiditis, 674. See also Hashimoto thyroiditis. lymphocytic, 674 neck pain associated with, 950 postpartum, 674, 739-740 Thyroid-stimulating hormone (TSH), 660, 662t, 664, 670 assay of, 671 autoantibodies to receptor for, 671-673 deficiency of, 662t, 664, 667 in hypothyroidism, 675-676 Thyrotoxic crisis, 672 Thyrotoxic periodic paralysis, 1188 Thyrotoxicosis, 672. See also Hyperthyroidism. factitious, 674 Thyrotropin. See Thyroid-stimulating hormone (TSH). Thyrotropin-releasing hormone (TRH), 661t, 664, 670 prolactin and, 663 Thyrotropin-secreting pituitary tumors, 662t, 664 Thyroxine. See Levothyroxine. Thyroxine-binding globulin (TBG), 670-671, 676 Ticlopidine, 581-582

Tics, 1111t, 1116 Tidal volume, 199, 200f control of, 203 in mechanical ventilation, 261 Tilt-table testing, 133-134 Tiludronate, for Paget disease of bone, 814-815, 815t TIMI risk score, 110 Tinnitus, 1100-1102, 1101f, 1105 Tiotropium, in chronic obstructive pulmonary disease, 217-218 Tirofiban, 582 Tissue factor, 555-556, 560, 561f Tissue factor pathway inhibitor, 561, 561f Tissue-type plasminogen activator (t-PA), 559f, 562 atherothrombosis and, 580-581, 582t, 587 recombinant (rt-PA) for cerebral venous sinus thrombosis, 1131-1132 for ischemic stroke, 1130-1131, 1131f for pulmonary embolism, 173 for reperfusion, in myocardial infarction, 112, 112t Titubation, 1111t, 1116 TLC (total lung capacity), 207-208, 207f TmP. See Tubular maximum for phosphorus (TmP). TNK-tPA (tenecteplase), 112, 112t TNM (tumor-node-metastasis) staging, 621 Tobacco. See Smoking. Todd paralysis, 1128, 1144 Tolbutamide, 708-709, 710t-713t Tolcapone, 1112, 1112t Toll-like receptors, 927 Tolvaptan, 344b Tonic movements, 1143 Tonic pupils, 1097 Tonic seizure, 1146 Tonsillitis, 948-950 Tooth infections, osteomyelitis in, 988 Tophi, 864, 866-868 Topiramate, 1149-1150, 1150t Torsades de pointes, 143 Torticollis, spasmodic, 1115t Tositumomab, 626t for follicular lymphomas, 544 Total body water, 305, 306f Total lung capacity (TLC), 207-208, 207f Total parenteral nutrition (TPN). See also Parenteral nutrition. in pancreatitis, acute, 450 in small bowel Crohn disease, 437 Tourette disorder, 1116, 1116t Toxic megacolon, 431 Toxic multinodular goiter, 674 Toxic myopathies, 1190, 1190t Toxic neuropathies, 1180 Toxic shock syndrome staphylococcal, 916 streptococcal, 916 Toxic thyroid adenoma, 673-674 Toxins. See also Poisoning. acidosis caused by, 318 RNA synthesis inhibited by, 4 scleroderma-like effects of, 847t Toxoplasma gondii, 889t Toxoplasmosis, 889t, 1039t cerebral, 942, 943f, 1159 in HIV-infected patients, 1022, 1023t, 1160 in HIV-infected patients cerebral, 1022, 1023t, 1160 prophylaxis against, 1019-1020, 1019t serologic testing for, 1016 mononucleosis syndrome in, 912-913, 919 t-PA. See Tissue-type plasminogen activator (t-PA). TPN. See Total parenteral nutrition (TPN). TPO. See Thrombopoietin (TPO); Thyroid peroxidase (TPO). Trachea, 198, 199f trans-acting factors, 5. See also Transcription factors. Transcription, 2-4, 3f inhibitors of, 4 regulation of, 3-6 Transcription factors, 4-6 disease phenotype and, 12 Transesophageal echocardiography (TEE), 57, 58f of atrial septal defect, 76-77 in infective endocarditis, 963 intraoperative, 280

Index Transesophageal echocardiography (TEE) (Continued) of mitral stenosis, 88-89 of prosthetic valve function, 93 Transfer RNA (tRNA) secondary structure of, 4f synthesis of, 2-3 in translation of code, 3f-4f, 4 Transferrin, 653-654 Transforming growth factor-β (TGF-β), in chronic kidney disease, 369-370 Transfusion of coagulation factors, 578-579, 578t of cryoprecipitate, 579 cytomegalovirus postperfusion syndrome following, 923 dilutional coagulopathy caused by, 573-574, 577 of fresh frozen plasma, 578 in gastrointestinal bleeding, 386-387 iron overload caused by, 504 in myelodysplastic syndrome, 504-505 of platelets. See Platelet transfusion. in sickle cell disease, 530-531 thrombocytopenia secondary to alloimmune, 570 dilutional, 571-572 for thrombotic thrombocytopenic purpura, 587 Transgenic animal, 10 Transient elastography, 459b Transient ischemic attack, 1125-1126, 1130 aneurysm-related, 1134 in anterior circulation, 1126-1127 differential diagnosis of, 1128 statin therapy after, 1132 treatment of, 1130, 1130f vertigo in, 1105 Transitional cell carcinoma, 611 Translation, 3-4, 3f cap of messenger RNA and, 3 inhibition of, by antibiotics, 4 regulation of, 5 Transmural infarction. See Myocardial infarction, ST-segment elevation (STEMI). Transmyocardial laser revascularization, 105 Transplant osteodystrophy, 800 Transplantation. See also Bone marrow transplantation; Cardiac transplantation; Kidney transplantation; Lung transplantation; Stem cell transplantation. immunosuppression secondary to, 553 lymphoproliferative disorder secondary to, 553 Transposition of great arteries, 81-82 Transthyretin, mutations in, 880 Transurethral incision of prostate, 756, 756t Transurethral microwave thermotherapy for benign prostatic hyperplasia, 755 for chronic pelvic pain syndrome, 758 Transurethral needle ablation, 755 Transurethral resection of prostate (TURP), 755-756, 756t bacterial infection and, 757-758 Transverse myelitis acute, 1169-1170 optic nerve disease with, 1099 Trastuzumab, 610, 621-622, 626t Trauma to aorta, 157-158 to brain. See Brain injury, traumatic. cardiac, 157-158, 157t headache secondary to, 1092 from interpersonal violence, 748 osteomyelitis secondary to, 988 pneumothorax caused by, 250 to spine. See Spinal cord injury, traumatic. transfusion in, 577 venous thromboembolism secondary to, 584 Traveler’s infections, 1034-1041 AIDS and, 1037 avian influenza as, 1036 diarrhea in. See Diarrhea, traveler’s. future prospects for, 1041b general advice on, 1036 helminthic, 1039-1041, 1040t immunizations against, 1034-1035 malaria as. See Malaria. overview of risks, 1034 pregnant women and, 1036-1037

Traveler’s infections (Continued) protozoal, 1038, 1039t in returning traveler, 1037-1038 Treadmill testing, 54-55. See also Stress testing. in angina pectoris, 101f Tremor, 1109, 1111t, 1114 essential tremor, 1109, 1114 intention tremor, 1111t, 1116 in Parkinson disease, 1109, 1112, 1114 Treponema, 885. See also Syphilis. Treprostenil, for pulmonary hypertension, in systemic sclerosis, 848-849 Tretinoin (all-trans-retinoic acid), for acute promyelocytic leukemia, 517, 626t TRH. See Thyrotropin-releasing hormone (TRH). Trichomonas vaginalis infection, 889t, 1004-1005, 1005t, 1039t in HIV-infected patients, 1021 Tricuspid regurgitation, 86t, 91 jugular venous pulse and, 36, 37f Tricuspid stenosis, 86t, 91 jugular venous pulse and, 36, 37f Tricuspid valve anatomy of, 22 Ebstein anomaly of, 78t, 79 infective endocarditis of, 962, 966 Tricyclic antidepressants, 1079t for chronic pelvic pain, male, 758 for fibromyalgia syndrome, 876-877 in narcolepsy, 1066 for neuropathic pain, 1178t overdose of, 264t tension-type headache and, 1090 Trientine, for Wilson disease, 652 Trigeminal autonomic cephalgia, 1088-1090, 1093 Trigeminal neuralgia, 1093 Triggered activity, cardiac, 119 Triglycerides, 643 in chronic kidney disease, 374-375 coronary artery disease and, 97 in diabetes management, 704 dyslipidemia and, 644-646 management of, 646, 647t specific disorders and, 649-650 in familial hypertriglyceridemia, 650 median-chain, 452 in metabolic syndrome, 631-632 metabolism of, 643-644 parenteral nutrition and, 641-642 Triptans, for migraine, 1088 Tropomyosin, 25 Troponin, 25 Troponins I and T, 107-108, 108f cardiac contusion and, 157 after noncardiac surgery, 280 Trousseau sign, 453, 609, 788 Trousseau syndrome, 171, 571, 585 Trypanosomiasis African, 1038, 1039t American, 1038, 1039t Trypsinogen, serum, 451 l-Tryptophan, eosinophilia-myalgia caused by, 847t TSH. See Thyroid-stimulating hormone (TSH). Tube feeding, 640. See also Enteral nutrition. end-of-life, 1216 Tuberculin testing, 257, 257t, 957. See also Purified protein derivative (PPD) test. HIV infection and, 958 pleural effusion and, 959 Tuberculosis, 256-257, 256f. See also Mycobacteria. adrenal insufficiency in, 680-681 arthritis in, 986 central nervous system manifestations of, 938-939, 941-942 in HIV-infected patients, 1023 spinal epidural abscess, 1162 cervical lymphadenitis in, 919 chemotherapy for, 958 febrile syndrome in, 912t, 914 fever of unknown origin and, 920-922 in HIV infection, 958, 1016, 1023-1024, 1024t hypercalcemia in, 786 immune defense against, 896-897 laboratory diagnosis of, 899 lymphadenopathy in, 919

1279

Tuberculosis (Continued) osteomyelitis in, chronic, 988 peritonitis in, 978, 978t pleural effusion in, 250 progressive primary, 957 prophylaxis against, 257, 257t, 958, 960 in HIV-infected patient, 1019, 1019t pulmonary, 256-257, 256f, 951, 957-958 pleural effusion in, 959 renal, 991 Tuberous sclerosis complex, 340, 1121 lymphangioleiomyomatosis in, 239 Tubular maximum for magnesium, 782 Tubular maximum for phosphorus (TmP), 780-781, 781f, 792 Tubular reabsorption of filtered phosphate, 780, 781f Tubules, renal functions of, 290t, 291 structure of, 286-290, 287f-288f Tubuloglomerular feedback, 289-290 Tubulointerstitial nephropathy, 301t, 302 Tularemia, 920 Tumor(s). See also Cancer; Nodules. cardiac, 156, 157t fever associated with, 922 renal, 339-340 Tumor lysis syndrome, 367 in acute myeloid leukemia, 514-515 with high-grade non-Hodgkin lymphomas, 545-546 hyperphosphatemia in, 791 prevention of, 868-869 Tumor markers, 621-622 in testicular cancer, 766, 766t Tumor necrosis factor-α, 928t from adipose tissue, 631, 700-701 alcoholic liver disease and, 471-472, 475b monoclonal antibodies against, 13 for Crohn disease, 437 latent tuberculosis and, 957 for rheumatoid arthritis, 827, 827t for spondyloarthropathies, 832 for Takayasu arteritis, 861 sarcoidosis and, 231-233 in spondyloarthropathies, 830 Tumor necrosis factor-α receptor, soluble, 13, 827t Tumor plop, 41, 42f Tumor suppressor genes, 595-596, 595t Tumoral calcinosis, 791-792 Tumor-node-metastasis (TNM) staging, 621 Tuning fork tests, 1101 Turner syndrome, 735-736 TURP. See Transurethral resection of prostate (TURP). T-wave abnormalities, 53, 54f T-wave inversion, 51-53 Typhoid, immunization of travelers against, 1035 Typhoid fever, 912t, 913 Typhus, murine, 916 Tyrosine kinase inhibitors, 594, 625-626, 626f, 626t. See also Imatinib (Gleevec). for lung cancer, 269 for renal cell carcinoma, 612 Tyrosine kinases, 595 Tzanck preparation, 899, 899f U U wave, 47 Ulcer(s) esophageal, 413 gastroduodenal. See also Peptic ulcer disease. NSAID gastropathy and, 417 stress-related, 417-418 genital, 998-1002, 999t. See also specific diseases. oral. See Oral ulcers and vesicles. Ulcerative colitis, 430. See also Inflammatory bowel disease. causes of, 430-431 clinical features of, 431-432 diagnosis of, 433, 433f-434f vs. Crohn disease, 435-436, 435t differential diagnosis of, 433-434 epidemiology of, 430

1280

Index

Ulcerative colitis (Continued) extraintestinal manifestations of, 434-435, 435t primary sclerosing cholangitis, 435, 493 treatment of, 436-438, 436t Ulcerative cutaneous lesions, 969, 970t, 971 diabetic foot ulcers, 718, 971-973 osteomyelitis secondary to, 988 in ecthyma gangrenosum, 970 osteomyelitis secondary to, 988, 988t stasis ulcers, 971 Ulceroglandular fever, 920 Ulnar palsy, 1175t, 1179 Ultrasonography abdominal, 405-406 in pain evaluation, 384 bladder, 302 calcaneal, for bone mass measurement, 804-805, 807t of carotid arteries, 1056 in cholecystitis, 491-492 of diaphragm paralysis, 210 Doppler. See Doppler ultrasonography. endobronchial, 211 endoscopic. See Endoscopic ultrasound. renal, 302 in acute kidney injury, 362-363 in cystic disease, 336-338 in nephrolithiasis, 341 in renal artery stenosis, 347 in urinary tract obstruction, 336 of thyroid, 671 transrectal, 754, 764 in urinary tract infection, 990-991 of vertebral arteries, 1056 Ultrasound, high-intensity focused, for prostate cancer, 765 Umbilical cord blood stem cell transplantation, 500, 625 Uncal herniation, 1155 Uncinate seizures, 1143 Universal precautions for blood and body fluids, 992, 1026 Unstable angina, 99t, 106-107 pain of, 32-33 plaque disruption and, 95 treatment of, 108-110, 109f u-PA (urokinase-type plasminogen activator), 562 Upper airway obstruction, flow-volume loops in, 208-209, 208f Upper endoscopy, 401, 403f. See also Endoscopy, gastrointestinal. Upper GI series, 405. See also Barium contrast studies. Upper motor neuron diseases. See also specific diseases. clinical spectrum of, 1173, 1173t signs and symptoms of, 1108, 1172 Upper respiratory tract infections epidemiology of, 190 sinusitis and, 946 viral, 912, 912t Urea, renal transport of, 296 Urea breath test, 421, 422f Ureaplasma urealyticum infection, 989-990, 1004-1005 Uremic syndrome clinical manifestations of, 372-375, 373f-374f etiologic factors of, 372, 372f platelet dysfunction in, 573, 579 Urethral syndrome, 990 Urethritis, 989 gonococcal, 1003-1004 nongonococcal, 1004-1005 reactive arthritis associated with, 830t, 831 Uric acid, metabolism of, 864-865, 865f Uric acid stones, 343, 867 Uric acid–lowering agents, 868, 868t Uricase, pegylated, for prevention of tumor lysis syndrome, 868-869 Urinalysis, 300-301, 301t in acute kidney injury, 361-363 in infection, 989-990 with renal calculi, 341, 341t Urinary diagnostic indices, in acute kidney injury, 362, 372t Urinary incontinence diabetic neuropathy with, 718 in older adults, 1203-1205, 1204t in women, 745

Urinary pH in acidosis, 299-300, 320 stone formation and, 342-343 Urinary tract imaging of, 302-303, 303t male lower tract symptoms, 752-753, 753f, 753t differential diagnosis of, 754 Urinary tract infections, 989-991. See also Prostatitis; Urethritis. catheter-associated, 993, 993t in chronic bacterial prostatitis, 757-758, 991 fever in, 922 in pregnancy, 368 struvite stones associated with, 343, 343t tuberculous, 991 Urinary tract obstruction, 336, 336t acute kidney injury in, 361 imaging in, 302-303, 303t interstitial nephritis in, 335 prostate and. See Benign prostatic hyperplasia (BPN). Urine culture, 990-991 Urine output, acute kidney injury and, 359b in acute tubular necrosis, 361 Urine sulfosalicylic acid test, 300 Urodynamic evaluation, in men, 754 Uroflowmetry, with male symptoms, 753-754 Urokinase-type plasminogen activator (u-PA), 562 Urothelial carcinoma, 611 Ursodeoxycholic acid for gallstones, 491 for primary sclerosing cholangitis, 493 Usual interstitial pneumonia, 227-230, 228t-229t, 233-234 Uterine bleeding abnormal, 740-741, 740t in perimenopause, 742, 742t dysfunctional, 741 Uveitis inflammatory bowel disease with, 435 in spondyloarthropathies, 829, 831-832 Uveoparotid fever, 232, 232t V Vaccines. See also Immunizations; Influenza vaccine; Meningococcal vaccine; Pneumococcal vaccine. conjugate, 895-896 against Haemophilus influenzae type b, 1030 against HIV, investigational, 1026-1027 poliovirus, 1034-1035 Vaccinia vaccination, 1047, 1047f Vagal tone cardiac impulses and, 118 sinus bradycardia and, 122 Vaginal bleeding. See Uterine bleeding, abnormal. Vaginitis, 1005, 1005t in HIV-infected patients, 1014-1015 Vaginosis, bacterial, 1005, 1005t in HIV-infected patients, 1021 Vagus nerve stimulator, 1150-1151 Valproate, 1149-1150, 1150t neural tube defects and, 1151-1152 Valsalva maneuver, cardiac auscultation and, 40t Valves, cardiac. See also Prosthetic heart valves. anatomy of, 22 cardiac cycle and, 26, 27f Valvular heart disease, 84-94. See also Endocarditis; Infective endocarditis. in antiphospholipid antibody syndrome, 841 causes of, in adults, 85t. See also specific causes. characteristic findings in, 86t congenital, 77-79 aortic valve, 77-79, 78t, 84-85 pulmonic valve, 78t, 79 tricuspid valve, 78t, 79 future prospects for, 94b multivalvular, 91-92 noncardiac surgery in patient with, 162, 281 prosthetic valves for. See Prosthetic heart valves. rheumatic, 92, 92t stroke prevention in, 1132 stroke risk in, 1128-1130

Valvular heart disease (Continued) surgery for, 159-160 in systemic lupus erythematosus, 835 van den Bergh reaction, 460 Vanishing testicle syndrome, 692 Vardenafil, 762 Variable number tandem repeats, 7-8 Variant (Prinzmetal) angina, 97-98, 99t, 105-106 electrocardiography in, 51-53, 99t, 105, 106f pain of, 32-33 Variceal hemorrhage, 479-481, 481f beta blockers and, 481, 486, 487b portal vein thrombosis with, 486 Varicella-zoster immune globulin, 970 Varicella-zoster virus infection, 917, 970-971 vs. smallpox, 1047 Varicocele, 768 Vasa recta, renal, 286, 290, 293, 345 Vascular dementia, 1074 Vascular endothelial growth factor (VEGF) anticancer agents targeting, 612, 625, 626t tumor angiogenesis and, 594 Vascular malformations, 169-170 of brain and spinal cord, 1134-1135 epilepsy associated with, 1147-1148 Vascular resistance. See Pulmonary vascular resistance; Systemic vascular resistance. Vasculitic neuropathies, 1175-1178 Vasculitis. See also Arteritis. antinuclear cytoplasmic antibodies in, 327 bleeding secondary to, 565-566 fever associated with, 922 leukocytoclastic, 862 paraneoplastic, 878 pulmonary, 235-237 renal arteries in, 350 rheumatoid arthritis with, 825-826 septic, 566 systemic, 858-863. See also specific disorders. classification of, 858, 859f clinical features of, 858-859, 859t differential diagnosis of, 862-863, 862t immunosuppressive therapy in, 863 large-vessel, 859f, 859t, 861-862 medium-vessel, 859f, 859t, 860-861 overview of, 858 pathogenesis of, 858, 859f small-vessel, 858-859, 859f, 859t in systemic lupus erythematosus, 835, 838 Vasoactive intestinal polypeptide, islet cell tumors secreting, 786 Vasoconstriction coronary artery, 29 hypoxic, 203 Vasodilation, coronary artery, 29 Vasodilators in aortic regurgitation, 87 direct, for hypertension, 179t-182t in heart failure, 72 refractory, 73 for hypertensive emergencies, 185, 185t for pulmonary hypertension, idiopathic, 243-244 Vasopressin, 30, 660. See also Antidiuretic hormone (ADH); Desmopressin (DDAVP). ACTH and, 679, 681f for gastrointestinal bleeding, 406, 421-422 in water deprivation test, 299 Vasopressin analogue, for hepatorenal syndrome type 1, 367 Vasopressin receptor antagonists for hyponatremia, 310-311 for refractory ascites, 482 Vasospastic angina. See Variant (Prinzmetal) angina. Vasovagal (neurocardiogenic) syncope, 133-134, 133t Vaughan Williams classification, 136, 136t Vegetative state, persistent, 1062-1063, 1062t VEGF. See Vascular endothelial growth factor (VEGF). Vena caval filter in cancer patients, 616 in deep venous thrombosis, 171-172 in pregnancy, 590 in trauma patients, 584, 587-588 with spinal cord injury, 1139 in venous thromboembolism, 587-588 perioperative care and, 590

Index Venous angioma, cerebral, 1134 Venous circulation, 30 Venous sinus thrombosis. See Cerebral venous sinus thrombosis. Venous thromboembolism, 171-174. See also Deep venous thrombosis; Pulmonary embolism. in antiphospholipid antibody syndrome, 841-842 cancer-associated, 585, 616 hemostatic balance and, 555 heparin-induced, 586 laboratory evaluation of, 587, 587t in myeloproliferative disorders, 585-586 in paroxysmal nocturnal hemoglobinuria, 502-503 portal vein, 485-486 in pregnancy, 590 prophylaxis of, 173-174, 587-588 in hospitalized cancer patient, 616 risk factors for, 580 acquired, 584-585, 584t inherited, 582-584, 582t in systemic lupus erythematosus, 835 therapy for, 587-590, 588t-589t. See also Anticoagulation. Venous waveforms, 36, 37f Ventilation, 199-200, 200f control of, 202-203, 203f distribution of, 202, 202f Ventilation-perfusion lung scan, 197 in pulmonary embolism, 172-173, 242, 242f, 243t Ventilation-perfusion mismatch, 205-206, 205f in chronic obstructive pulmonary disease, 217 in interstitial lung diseases, 226 mixed venous Po2 and, 207f pulmonary embolism with, 241 Ventilation-perfusion ratio, mechanical ventilation and, 259-260 Ventilator. See Mechanical ventilation. Ventilator-associated pneumonia, 255, 994-995 Ventricular aneurysm, 116, 143 Ventricular assist devices, 74. See also Mechanical circulatory assist devices. as bridge to transplantation, 160 in cardiogenic shock, 115 Ventricular diastolic gallop, 41 Ventricular fibrillation, 130f, 131 defibrillation of, 141 in dilated cardiomyopathy, 151 in hypertrophic cardiomyopathy, 153 implantable cardioverter-defibrillator and, 142-143 myocardial infarction complicated by, 113 sudden cardiac death caused by, 135, 135t Ventricular flutter, 131 Ventricular free-wall rupture, 116 Ventricular hypertrophy. See Left ventricular hypertrophy; Right ventricular hypertrophy. Ventricular premature complexes, 121-122, 121f Ventricular pressures, 26-27, 27f, 27t Ventricular septal defect, congenital, 76f, 76t, 77 in tetralogy of Fallot, 81 Ventricular septal defect, postinfarction, 116 Ventricular tachyarrhythmias, 130-131, 130f. See also Ventricular fibrillation; Ventricular flutter; Ventricular tachycardia. defibrillation for, 141 direct current cardioversion for, 141 implantable cardioverter-defibrillators and, 142-143 sudden cardiac death caused by, 135, 135t Ventricular tachycardia, 130-131, 130f adenosine-sensitive, 130 cardiomyopathy secondary to, 151 cardioversion for, 141 diagnostic features of, 132, 132t in dilated cardiomyopathy, 151 in hypertrophic cardiomyopathy, 153 implantable cardioverter-defibrillator and, 142-143 myocardial infarction complicated by, 113 nonsustained, 130-131 radiofrequency catheter ablation for, 130-131, 142 sudden cardiac death caused by, 135, 135t surgical therapy for, 143 sustained, 130-131 as torsades de pointes, 143 verapamil-sensitive, 130

Ventriculography cardiac catheterization with, 60 radionuclide, 57 Ventriculoperitoneal shunt for idiopathic intracranial hypertension, 1092 for normal-pressure hydrocephalus, 1075 Verapamil, after myocardial infarction, 111 Vertebral arteries, 1123-1124, 1124f Vertebrobasilar ischemia, 1127 Vertebrobasilar occlusion, 1127, 1127t Vertebroplasty, 809-810 Vertigo, 1104-1107 approach to patient with, 1104-1107 benign paroxysmal positional, 1104-1105, 1105t, 1106f definition of, 1105-1106 in Ménière disease, 1102, 1105, 1105t migrainous, 1087 symptomatic treatment of, 1107 vestibular functioning and, 1104 in vestibular neuritis, 1104-1105, 1105t vestibular schwannoma with, 1101-1102 Very-low-density lipoprotein (VLDL), 643-644, 644f, 644t. See also Dyslipidemia. Vesicles cutaneous, 969, 970t oral. See Oral ulcers and vesicles. Vestibular neuritis, 1104-1105, 1105t Vestibular schwannoma, 1101-1102, 1102f Vestibular system basic concepts of, 1104 peripheral disorders of, 1104-1105, 1106f Vibrio cholerae infection, 397-398, 979-980, 981t, 984 prevention of, 1035-1036 Vibrio parahaemolyticus infection, 980-981, 984 Video capsule endoscopy, 402, 407b in Crohn disease, 433 varices and, 481 Video esophagogram, 405 Vincent stomatitis, 947 Vincristine, 623t Vinyl chloride, scleroderma-like effects of, 847t VIPoma, 786 Virchow triad, 171, 580 Viruses, 884 host defense against, 897 laboratory isolation of, 902 Visceral pain, 382 Visceral pleura, 248 Visual acuity, 1096 Visual evoked potentials, in multiple sclerosis, 1166, 1167t Visual fields, 1096, 1097f Visual hallucinations, 1096, 1099-1100 in diffuse Lewy body disease, 1113 Visual illusions, 1099-1100 Visual loss. See also Blindness. bilateral, 1099-1100 giant cell arteritis with, 1092 in idiopathic intracranial hypertension, 1092 in older adults, 1203 unilateral, 1098-1099 Visual system, examination of, 1096-1098, 1097f-1098f Vital capacity, 207, 207f Vitamin A hypercalcemia caused by, 786 idiopathic intracranial hypertension and, 1099 Vitamin B2, for migraine prevention, 1088 Vitamin B6 (pyridoxine), peripheral neuropathy caused by, 1177 Vitamin B12 (cobalamin) deficiency of, 524-525, 524t in Crohn disease, 432, 437 neuropathy caused by, 1177 intrinsic factor and, 415-416, 524-525 metabolic pathways of, 524, 524f in Schilling test, 391-392 Vitamin C deficiency of, 565-566 renal calculi associated with, 343 Vitamin D, 773, 776-777, 776f chronic kidney disease and, 374, 374f deficiency of, hypophosphatemia in, 792-793 granulomatous activation of, 786

1281

Vitamin D (Continued) hypercalcemia caused by, 786 hypercalciuria and, 342 hypocalcemia in disorders of, 788t, 789-790 osteomalacia and, 789-790, 793, 798 renal functions and, 292-294, 297 supplementation of in hyperparathyroidism, 800 in hypoparathyroidism, 789 for osteoporosis prevention, 805-807 in Paget disease of bone, 815-816 in renal osteodystrophy, 798-799 tumor secretion of, 785 Vitamin E, in Wilson disease, 652 Vitamin K coagulation factors and, 561, 564 deficiency of, 577 replacement of in coagulopathy, 578 in fulminant hepatic failure, 476-477 in heparin-induced thrombocytopenia, 586 Vitamin supplements. See Nutritional supplements. VLDL. See Very-low-density lipoprotein (VLDL). Voice sounds, 195, 196t Volume disorders. See also Edema. with decreased ECV and increased ECF, 306, 307t volume depletion, 306-307, 307t metabolic alkalosis secondary to, 321 volume excess, 307-308, 307t therapy of, in glomerular disease, 325 Volume homeostasis, 305-306, 306f Vomiting chemotherapy-induced, 627 headache with, 1091 metabolic alkalosis secondary to, 321 von Hippel–Lindau disease, 340, 1122 von Willebrand disease, 572t, 574-575, 575t, 577-579 von Willebrand factor, 555-556, 556f, 558-560 defects in, 574-575, 575t in factor VIII concentrate, 579 hemolytic uremic syndrome and, 355f thrombotic thrombocytopenic purpura and, 353, 354f W Waist-to-hip circumference ratio, 630 Wakefulness-promoting agents, 1066, 1066t Waldenström macroglobulinemia, 550, 550t, 552-553 hypercalcemia in, 787 skeletal demineralization in, 800 Walk test, 6-minute, 195-197, 209, 217 Wall motion abnormalities in angina pectoris, 99, 101 in dobutamine stress echocardiography, 55, 276 in myocardial infarction, 107 pathophysiology of, 98 Wall stress Laplace’s law for, 28 left atrial, electrocardiography in, 50, 50t left ventricular, in heart failure, 68 myocardial oxygen consumption and, 28 Wallenberg syndrome, 1126 Warfarin after acute coronary syndrome, 116-117 in antiphospholipid antibody syndrome, 356, 842-843 in atrial fibrillation, 126 for cardioversion, 141 bacterial endocarditis and, 1128-1130 in cancer patients, 616 after cerebral venous sinus thrombosis, 1131-1132 for deep venous thrombosis, 171, 173 drugs affecting level of, 589-590, 589t, 590b in heart failure, 73 in heparin-induced thrombocytopenia, 586 international normalized ratio and, 561-562 mechanism of action, 561, 577 perioperative care and, 590 for portal vein thrombosis, 486 pregnancy and, 590 prosthetic valves and, 163 for prophylaxis of venous thromboembolism, 173-174

1282

Index

Warfarin (Continued) with prosthetic heart valves, 92-93 noncardiac surgery and, 281 in pregnancy, 163 for pulmonary embolism, 173 for renal vein thrombosis, 357 reversal of, with fresh frozen plasma, 578 skin necrosis induced by, in protein C or S deficiency, 583-584 for stroke prevention primary, 1128-1130 secondary, 1132 for venous thromboembolism, 583-584, 588-590, 589t Warm immune hemolysis, 527 Warts, genital, 999t, 1006 Wasting. See Cachexia. Water osmolality regulation and, 308-309, 309f reabsorption by kidneys, 296 total body, 305, 306f Water brash, 408-409 Water deficit, 312 Water deprivation test, 299, 668 Water-hammer pulse, 36-38 Watershed ischemia, 1127 Weakness. See also Cachexia; Fatigue. in motor system disease, 1108 in neuromuscular disease, 1172t, 1177 myopathies, 1182-1184 Weber syndrome, 1126 Webs, esophageal, 411-412 Websites, medical, 18-19, 19t Wegener granulomatosis, 225, 231, 236, 327, 859-860, 859f Weight loss, involuntary in acute tubular necrosis, 363-364 nutritional assessment in, 638 in older adults, 1205 Weight management after acute coronary syndrome, 116-117 approaches for, 632-634, 632t, 633f by diabetic patient, 705 in metabolic syndrome, 715 risk reduction associated with, 631-632

Wenckebach phenomenon, 122-123, 123f-124f Wernicke aphasia, 1068, 1070t, 1127 Wernicke encephalopathy, 1071, 1224 hypothermia in, 1083 West Nile virus, 912, 940-941 West syndrome, 1146-1147 Westermark sign, 172, 242 Wheezing, 192-193, 195 Whipple disease, 880 Whipple procedure, 609 Whipple triad, 721 Whispered pectoriloquy, 195 White cell count, 535-536 Whitlow, herpetic, 970 Wide-complex tachycardia, 132 Wilson disease, 474-475, 477, 651-652, 652t, 1114-1115 Wiskott-Aldrich syndrome, 567 Wolff-Parkinson-White syndrome, 128f, 129-130 Women’s health, 730-749. See also Cardiovascular disease, in women. in adolescence, 734-736 breast complaints in, 746-747 causes of death and, 731-732 diabetes in, 746 differences from men and biologic, 731-733 social and economic, 733 intimate partner violence and, 747-748, 748t obesity and, 746 overview of, 730-731 pelvic pain and, 747 preventive health recommendations, 733, 734t Women’s Health Initiative (WHI), 16-17, 731, 743, 809 Women’s reproductive care, 736-742. See also Pregnancy. cervical cancer screening in, 741-742 contraception in, 737-738, 737t. See also Oral contraceptives. history of pregnancy complications and, 739 infertility in, 741 menstrual cycle abnormalities in, 740-741, 740t. See also Amenorrhea.

Women’s reproductive care (Continued) postpartum, 739-740 preconception, 736-737 prescribing medication in, 738-739, 738t-739t sexual history in, 737 Women’s reproductive physiology, 732f, 733 Wright test, 171 Writer’s cramp, 1115t X Xanthomas, in familial hypercholesterolemia, 648 X-chromosome inactivation, 6 Xerophthalmia. See Keratoconjunctivitis sicca. Xerostomia differential diagnosis of, 856-857 in Sjögren syndrome, 855-856, 856t treatment of, 857, 857t X-linked disorders, 11t, 12 d-Xylose test, 391, 394 Y Yeast, 888. See also Fungal infections; Fungal pathogens. Yellow fever, immunization against, 1034-1035 Yersinia enterocolitica infection, 981, 981t, 984 Yersinia pestis infection, 920, 1044-1045, 1047-1048 Z Zinc, for Wilson disease, 652 Zoledronate, for Paget disease of bone, 814-816, 815t Zoledronic acid, for osteoporosis prevention and treatment, 807-808, 808t Zollinger-Ellison syndrome, 419-420, 426-427 Zonisamide, 1149-1150, 1150t Zoster. See Herpes zoster. Zygomycetes, 888

Andreoli and Carpenter's Cecil Essentials of Medicine, 8th Edition (Cecil Medicine)

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